Condensed heterocyclic derivates as BCL-2 inhibitors for the treatment of neoplastic diseases

ABSTRACT

The disclosure includes compounds of Formula (A):wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12, j, k, m, n, Y, W, W1, W2, W3, V, L, Z1, Q1, Q2, Q3, and Q4, are defined herein. Also disclosed is a method for treating a neoplastic disease, an autoimmune disease, or a neurodegenerative disease with these compounds.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/795,884, filed on Feb. 20, 2020, which is a continuation applicationof International Patent Application No.: PCT/US2018/047411, filed onAug. 22, 2018, which claims the benefit of the filing date of U.S.Provisional Application No. 62/549,081, filed on Aug. 23, 2017; and U.S.Provisional Application No. 62/615,007, filed on Jan. 9, 2018. Theentire contents of each of the aforementioned applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Apoptosis, or programmed cell death, is a conserved and regulatedprocess that is the primary mechanism for the removal of aged, damagedand unnecessary cells. The ability to block apoptotic signaling is a keyhallmark of cancer and is thus important for oncogenesis, tumormaintenance and chemoresistance [Hanahan, D. & Weinberg, R. A. Thehallmarks of cancer. Cell 100, 57-70 (2000).]. Dynamic bindinginteractions between prodeath (for example, BCL-2-associated X protein(BAX), BCL-2 antagonist/killer 1 (BAK), BCL-2-associated agonist of celldeath (BAD), BCL-2-like 11 (BIM), NOXA and BCL-2 binding component 3(PUMA)) and prosurvival (BCL-2, BCL-XL, BCL-2-like 2 (BCL-W), myeloidcell leukemia sequence 1 (MCL-1) and BCL-2-related protein A1 (BFL-1))proteins in the BCL-2 family control commitment to programmed celldeath. Altering the balance among these opposing factions provides onemeans by which cancer cells undermine normal apoptosis and gain asurvival advantage [Youle, R. J. & Strasser, A. The BCL-2 proteinfamily: opposing activities that mediate cell death. Nat. Rev. Mol. CellBiol. 9, 47-59 (2008)].

BCL-2, the first identified apoptotic regulator, was originally clonedfrom the breakpoint of a t(14;18) translocation present in human B celllymphomas [Tsujimoto, Y., et al. Science 228, 1440-1443 (1985); Cleary,M. L., et al Cell 47, 19-28 (1986); Boise, L. H. et al. Cell 74, 597-608(1993)]. This protein has since been shown to have a dominant role inthe survival of multiple lymphoid malignancies [Vaux, D. L., et al pre-Bcells. Nature 335, 440-442 (1988)]. Overexpression of Bcl-2 proteinscorrelates with resistance to chemotherapy, clinical outcome, diseaseprogression, overall prognosis or a combination thereof in variouscancers and disorders of the immune system. Involvement of Bcl-2proteins in bladder cancer, brain cancer, breast cancer, bone marrowcancer, cervical cancer, chronic lymphocytic leukemia, colorectalcancer, esophageal cancer, hepatocellular cancer, lymphoblasticleukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cellorigin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovariancancer, non-small cell lung cancer, prostate cancer, small cell lungcancer, spleen cancer, and the like is described in PCT/US2004/36770,published as WO 2005/049593, and PCT/US2004/37911, published asWO/2005/049594. Involvement of Bcl-2 proteins in immune and autoimmunediseases is described in Current Allergy and Asthma Reports 2003, 3,378-384; British Journal of Hematology 2000, 110(3), 584-90; Blood 2000,95(4), 1283-92; and New England Journal of Medicine 2004, 351(14),1409-1418. Involvement of Bcl-2 proteins in arthritis is disclosed in WO2009/064938. Involvement of Bcl-2 proteins in bone marrow transplantrejection is disclosed in US 2008-0182845 A1. All incorporated herein byreference.

In the last decade, several Bcl-2 inhibitors such as ABT-737, ABT-263,and ABT-199 as shown below have been identified and entered humanclinical trials for cancers treatment.

ABT-737 is discovered by nuclear magnetic resonance (NMR)-basedscreening, parallel synthesis and structure based fragment drug design[Tillman Oltersdorf, et al, Nature, Vol 435, 2005, p 677]. ABT-737 asmall-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XLand Bcl-w, with an affinity two to three orders of magnitude more potentthan previously reported compounds. Mechanistic studies reveal thatABT-737 does not directly initiate the apoptotic process, but enhancesthe effects of death signals, displaying synergistic cytotoxicity withchemotherapeutics and radiation. ABT-737 exhibitssingle-agent-mechanism-based killing of cells from lymphoma andsmall-cell lung carcinoma lines, as well as primary patient-derivedcells, and in animal models, ABT-737 improves survival, causesregression of established tumors, and produces cures in a highpercentage of the mice. Unfortunately, ABT-737 is not orallybioavailable, and its formulation for intravenous delivery is hamperedby its low aqueous solubility.

After extensive MedChem effort, an orally bioavailable Bcl-2 inhibitorABT-263 (Navitoclax) has been developed [Cheol-Min Park, et al J. Med.Chem. 2008, 51, 6902-6915]. ABT-263 is a potent inhibitor of Bcl-xL,Bcl-2 and Bcl-w with Ki of ≤0.5 nM, ≤1 nM and ≤1 nM. ABT-263 has an IC₅₀of 110 nM against SCLC H146 cell line. When ABT-263 is administered at100 mg/kg/day in the H345 xenograft model, significant antitumorefficacy is observed with 80% TGI and 20% of treated tumors indicatingat least a 50% reduction in tumor volume. Oral administration of ABT-263alone causes complete tumor regressions in xenograft models ofsmall-cell lung cancer and acute lymphoblastic leukemia [Tse C, et al.Cancer Res. 2008, 68(9), 3421-3428]. In the clinical trial, however, theinhibition of BCL-XL by ABT-263 (navitoclax) induces a rapid,concentration-dependent decrease in the number of circulating platelets.This mechanism-based thrombocytopenia is the dose-limiting toxicity ofsingle-agent navitoclax treatment in patients and limits the ability todrive drug concentrations into a highly efficacious range.

Thus, a BCL-2 selective (BCL-XL sparing) inhibitor would culminate insubstantially reduced thrombocytopenia while maintaining efficacy inlymphoid malignancies. The resulting increase in the therapeutic windowshould allow for greater BCL-2 suppression and clinical efficacy inBCL-2-dependent tumor types. After extensive MedChem, ABT-199 (GDC-0199)has been successfully developed [Andrew J Souers, et al, NatureMedicine, Volume 19, 22, p 202, 2013]. ABT-199 is a Bcl-2-selectiveinhibitor with Ki of <0.01 nM, >4800-fold more selective versus Bcl-xLand Bcl-w, and no activity to Mcl-1. ABT-199 potently inhibits RS4;11cells with EC₅₀ of 8 nM. In addition, ABT-199 induces a rapid apoptosisin RS4;11 cells with cytochrome c release, caspase activation, and theaccumulation of sub-G0/G1 DNA. Quantitative immunoblotting reveals thatsensitivity to ABT-199 correlated strongly with the expression of Bcl-2,including NHL, DLBCL, MCL, AML and ALL cell lines. ABT-199 also inducesapoptosis in CLL with an average EC₅₀ of 3.0 nM. A single dose of 100mg/kg of ABT-199 causes a maximal tumor growth inhibition of 95% andtumor growth delay of 152% in RS4;11 xenografts. ABT-199 also inhibitsxenograft growth (DoHH2, Granta-519) as a single agent or in combinationwith Bendamustine and other agents. Human Phase I and II data showedthat ABT-199 is highly efficacious for CLL who have 17p deletion, andwas approved by FDA in 2016.

WO/2017/132474 discloses a novel class of BCL-2 inhibitors. However,there is still a strong need for continuing search in this field of artfor more potent BCL-2 inhibitor.

SUMMARY OF THE INVENTION

In a first embodiment, this invention provides compounds of the Formula(A) or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug of said compound of Formula (A) or N-oxide thereof:

wherein

Q₁ is 7-membered heterocycloalkyl, 7-membered heterocycloalkenyl, or7-membered heteroaryl;

Q₂ is an aryl or heteroaryl;

Q₃ is a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,aryl, or heteroaryl;

Q₄ is

each of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂,independently, is H, D, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,halo, nitro, oxo, cyano, OR_(a), SR_(a), alkyl-R_(a), NH(CH₂)_(p)R_(a),C(O)R_(a), S(O)R_(a), SO₂R_(a), C(O)OR_(a), OC(O)R_(a), NR_(b)R_(c),P(O)R_(b)R_(c), alkyl-P(O)R_(b)R_(c), C(O)N(R_(b))R_(c),N(R_(b))C(O)R_(c), —S(O)(═N(R_(b)))R_(c), —N═S(O)R_(b)R_(c),SO₂N(R_(b))R_(c), or N(R_(b))SO₂R_(c), in which said cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl isoptionally substituted with one or more R_(d);

R_(a), R_(b), R_(c), and R_(d), independently, is H, D, alkyl, alkenyl,alkynyl, halo, cyano, amine, nitro, hydroxy, ═O, C(O)NHOH, C(O)OH,C(O)NH₂, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl,alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, alkylamino, oxo,halo-alkylamino, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl, in which said alkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,heteroaryl is optionally substituted with one or more R_(e);

R_(e) is H, D, alkyl, alkenyl, alkynyl, halo, cyano, amine, nitro,hydroxy, ═O, C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl,aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino,alkylamino, oxo, halo-alkylamino, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

Z₁ is a bond, (CH₂)_(p), N(H), O, S, C(O), S(O₂), OC(O), C(O)O, OSO₂,S(O₂)O, C(O)S, SC(O), C(O)C(O), C(O)N(H), N(H)C(O), S(O₂)N(H),N(H)S(O₂), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S,N(H)C(O)N(H), (CH₂)_(p)N(H)(CH₂)_(q), (CH₂)_(p)N(H)C(O)(CH₂)_(q),(CH₂)_(p)C(O)N(H)(CH₂)_(q), OC(O)N(H)(CH₂)_(p+1)N(H)(CH₂)_(q), abivalent alkenyl group, or a bivalent alkynyl group;

L is a bond, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which saidalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,aryl, or heteroaryl is optionally substituted with one or more R_(d);

each of Y, W, W₁, and W₂, independently, is CH or N;

W₃ is O or N(R_(a));

V is N, C, or CH;

two of R₉ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₉, is optionally substitutedwith one or more R_(d);

two of R₂ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₂, is optionally substitutedwith one or more R_(d);

two of R₁₀ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₁₀, is optionally substitutedwith one or more R_(d);

R₁₁ and R₁₂ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₁₁ or R₁₂, is optionallysubstituted with one or more R_(d);

R₁₀ and R₂ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R₁₀ or R₂, is optionallysubstituted with one or more R_(d);

R₄ and —Z₁-L-R₆ group, taken together with the atom to which they areattached, may optionally form a cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, in which saidcycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, orheteroaryl of R₄, is optionally substituted with one or more R_(d);

R_(b) and R_(c) group, taken together with the atom to which they areattached, may optionally form a cycloalkyl, or heterocycloalkyl, inwhich said cycloalkyl or heterocycloalkyl of R_(b) and R_(c), isoptionally substituted with one or more R_(e);

two of R_(d) group, taken together with the atom to which they areattached, may optionally form a cycloalkyl, or heterocycloalkyl, inwhich said cycloalkyl or heterocycloalkyl of R_(d) is optionallysubstituted with one or more R_(e);

two of R_(e) group, taken together with the atom to which they areattached, may optionally form a cycloalkyl or heterocycloalkyl, in whichsaid cycloalkyl or heterocycloalkyl of R_(e) is optionally substitutedwith one or more groups selected from H, D, alkyl, alkenyl, alkynyl,halo, cyano, amine, nitro, hydroxy, C(O)NHOH, alkoxy, alkoxyalkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl,alkylcarbonylamino, alkylamino, oxo, halo-alkylamino, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

each of j and k, independently, is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and

each of m, n, p, q, and r, independently, is 0, 1, 2, 3, or 4.

In a second embodiment, the invention provides a compound represented byFormula (B):

or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug ofsaid compound of Formula (B) or N-oxide thereof, wherein

Z₂ is —O—, —CH₂—, —C(O)—, —N(R_(a))—, —S—, —S(O)—, —S(O₂)—,—S(O)(═N(R_(a)))—, —P(O)(R_(a))—; wherein R_(a) of Z₂, independently, isH, D, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkylcarbonyl, C₁-C₆alkoxycarbonyl,C₃-C₆cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C₆-C₁₄aryl,or 5-8 membered monocyclic heteroaryl, in which said C₁-C₆alkyl,C₃-C₆cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, C₆-C₁₄aryl,5-8 membered monocyclic heteroaryl is optionally substituted with one ormore Re, and

A is —(CR₂R₂)_(r)— or —O—; wherein r is 0, 1, 2, or 3;

-   -   each R₂ independently is H, —(C₁-C₄)alkoxy, —(C₁-C₄)alkyl        optionally substituted with —(C₁-C₄)alkoxy, or        -   two of R₂ groups, taken together with the same carbon atom            to which they are attached, form —(C₃-C₆)cycloalkyl or 4-6            membered heterocyclic ring, wherein the —(C₃-C₆)cycloalkyl            or 4-6 membered heterocyclic ring is optionally substituted            with one or more groups selected from —(C₁-C₄)alkyl,            —(C₁-C₄)haloalkyl or oxetanyl; and the remaining variables            are as defined in the first embodiment.

In a third embodiment, the invention provides a compound represented byFormula (C):

or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug ofsaid compound of Formula (C) or N-oxide thereof, wherein R₁ is H, D,halo or —(C₁-C₄)alkyl, and the remaining variables are as defined in thefirst and/or second embodiments.

In a fourth embodiment, the invention provides a compound represented byFormula (D):

or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug ofsaid compound of Formula (D) or N-oxide thereof, wherein

R₅ independently, is nitro, halo, or —SO₂R_(a), wherein R_(a) of R₅ is—(C₁-C₄)alkyl or —(C₁-C₄)haloalkyl (e.g., —CF₃); and

Z₁ is bond, NH, N(H)(CH₂)_(q), O, S, or —(C₁-C₄)alkylene, wherein q is1, 2, or 3;

L is absent or —(C₁-C₄)alkylene optionally substituted with—(C₃-C₆)cycloalkyl; and

R₆ is H, D, —N(CH₃)—(C₁-C₄)alkylene-P(O)((C₁-C₄)alkoxy)₂,—P(O)(N(CH₃)₂)(OEt), —P(O)(O—(C₁-C₄)alkylene-O—CO—(C₁-C₄)alkyl)₂,—(C₃-C₆)cycloalkyl, phenyl, 5-7 membered heterocyclyl, 8-10 memberedbicyclic ring, wherein the —(C₃-C₆)cycloalkyl, phenyl, 5-7 memberedheterocyclyl, or 7-10 membered bicyclic ring is optionally substitutedwith one or more groups selected from halo, —OH, ═O, —CN, —COOH, —NH₂,—N(CH₃)₂, —NS(═O)(CH₃)₂, —SO₂(C₁-C₄)alkyl, —(C₁-C₄)alkyl,—(C₁-C₄)alkoxy, —(C₁-C₄)haloalkoxy, cyclopropyl, 4-6 memberedheterocyclyl, —CH₂P(O)(OH)₂, —CH₂P(O)((C₁-C₄)alkoxy)₂,—P(O)((C₁-C₄)alkyl)₂, or —N═S(O)((C₁-C₄)alkyl)₂, and the remainingvariables are as defined in the first, second, and/or third embodiments.

In a fifth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of Formulaor N-oxide thereof, wherein R₉ independently, is D, halo, —OH, CN, —NH₂,═O, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —(C₁-C₄)haloalkyl,—(C₁-C₄)hydroxyalkyl, —(C₃-C₆)cycloalkyl, or 1,3-dithiolanyl; and k is0, 1, 2, 3, or 4; and the remaining variables are as defined in thefirst, second, third, and/or fourth embodiments.

In a sixth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D, or N-oxide thereof, wherein A is —CH₂— or —O—; and theremaining variables are as defined in the first, second, third, fourth,and/or fifth embodiments.

In a seventh embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein each R₂ independently is —CH₃;and n is 0 or 2; and the remaining variables are as defined in thefirst, second, third, fourth, fifth and/or sixth embodiments.

In an eighth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D, or N-oxide thereof, wherein Z₂ is —O—; and the remainingvariables are as defined in the first, second, third, fourth, fifth,sixth and/or seventh embodiments.

In a ninth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D, or N-oxide thereof, wherein R₁ is halo, such as Cl; andthe remaining variables are as defined in the first, second, third,fourth, fifth, sixth, seventh, and/or eighth embodiments.

In a tenth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein R₅ is nitro; and the remainingvariables are as defined in the first, second, third, fourth, fifth,sixth, seventh, eighth, and/or ninth embodiments.

In an eleventh embodiment, the invention provides a compound accordingto Structural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein Z₁ is absent, NH or O; and theremaining variables are as defined in the first, second, third, fourth,fifth, sixth, seventh, eighth, ninth, and/or tenth embodiments.

In a twelfth embodiment, the invention provides a compound according toStructural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein Z₂ is —O—, —CH₂—, —C(O)—,—NH—, —N-(oxetanyl)-, —S—, —S(O)—, —S(O₂)—, —S(O)(═NH)—, —S(O)(═NCH₃)—,or —P(O)(CH₃)—; and the remaining variables are as defined in the first,second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth,and/or eleventh embodiments.

In a thirteenth embodiment, the invention provides a compound accordingto Structural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein R₆ is H, D,—(C₃-C₆)cycloalkyl, phenyl, tetrahydro-2H-pyranyl, or 1,4-dioxanyl,wherein the —(C₃-C₆)cycloalkyl, phenyl, tetrahydro-2H-pyranyl or1,4-dioxanyl is optionally substituted with 1 or 2 groups selected fromhalogen, —OH, ═O, —(C₁-C₄)alkyl, or —(C₁-C₄)alkoxy; and the remainingvariables are as defined in the first, second, third, fourth, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, and/or twelfthembodiments.

In a fourteenth embodiment, the invention provides a compound accordingto Structural Formula A, B, C, or D, or an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, an isotopic form, or a prodrug of said compound of FormulaA, B, C, or D or N-oxide thereof, wherein R₆ is tetrahydro-2H-pyranyl or1,4-dioxanyl, wherein the tetrahydro-2H-pyranyl or 1,4-dioxanyl isoptionally substituted with 1 or 2 halogen; and the remaining variablesare as defined in the first, second, third, fourth, fifth, sixth,seventh, eighth, ninth, tenth, eleventh, twelfth, and/or thirteenthembodiments.

For example, in a compound according to Structural Formula A, B, C, orD, or an N-oxide thereof, or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug of said compound of Formula A, B, C, or D or N-oxide thereof, Z₁is —NH—, L is —CH₂—, R₆ is tetrahydro-2H-pyranyl or 1,4-dioxanyloptionally substituted with 1 or 2 groups of halogen, and, preferably Ais —CH₂— or —O—, R₁ is Cl, R₅ is nitro, Z₂ is —O—, each R₂ independentlyis —CH₃ and n is 0 or 2, and R₉ is methyl (and k is 1) or halo (and k is2, such as di-fluoro).

A modified compound of any one of such compounds including amodification having an improved (e.g., enhanced, greater) pharmaceuticalsolubility, stability, bioavailability, and/or therapeutic index ascompared to the unmodified compound is also contemplated. Exemplarymodifications include (but are not limited to) applicable prodrugderivatives, and deuterium-enriched compounds.

Also within the scope of this invention is a pharmaceutical compositioncontaining one or more of the compounds (such as any one of those inFormulae (A)-(D), or a pharmaceutically acceptable salt, solvate,polymorph, tautomer, stereoisomer, an isotopic form, or a prodrugthereof or an N-oxide thereof), modifications, and/or salts thereofdescribed herein, and a pharmaceutically acceptable diluent or carrier,for use in treating a neoplastic disease, therapeutic uses thereof, anduse of the compounds for the manufacture of a medicament for treatingthe disease/disorder.

This invention also relates to a method of treating a neoplasticdisease, an autoimmune disease, or a neurodegenerative disease,comprising administering to a subject in need thereof an effectiveamount of one or more compounds of the invention (such as any one ofthose in Formulae (A)-(D), or a pharmaceutically acceptable salt,solvate, polymorph, tautomer, stereoisomer, an isotopic form, or aprodrug thereof or an N-oxide thereof), modifications, and/or saltsthereof described herein, or a pharmaceutical composition comprising thecompound(s) of the invention.

In certain embodiments, the neoplastic disease, autoimmune disease, orneurodegenerative disease is characterized by abnormal (e.g., enhancedor increased) Bcl-2 activity. For example, the neoplastic disease can bea hematological malignancy or cancer including solid tumor; theautoimmune disease can be type I diabetes; and the neurodegenerativedisease can be schizophrenia.

In certain embodiments, the neoplastic disease is myeloma, multiplemyeloma, lymphoma, follicular lymphoma (FL), non-Hodgkin's lymphoma,leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) (such asBCL-2-dependent ALL and pediatric ALL), chronic lymphoblastic leukemia(CLL) (such as relapsed/refractory CLL, del(17p) CLL), chronic myeloidleukemia (CML) (such as blast-crisis CML), mantle cell lymphoma (MCL),diffuse large B-cell lymphoma, lung cancer such as small cell lungcancer (SCLC), melanoma, breast cancer, or prostate cancer, includingdrug-resistant cancer thereof.

In certain embodiments, the method further comprises administering oneor more further treatment(s) effective to treat the neoplastic disease,such as surgery, radiation therapy, a chemotherapeutic agent (such asbendamustine, NL-101(7-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)-N-hydroxyheptanamide),cisplatin, carboplatin, etoposide, topotecan), a target therapy (e.g.,an anti-CD20 antibody such as rituximab, a Bruton's tyrosine kinaseinhibitor such as ibrutinib and acalabrutinib (ACP-196), a PI3Kδinhibitor such as idelalisib); an antibody-drug conjugate or ADC (suchas anti-CD30 ADC brentuximab vedotin), an immunotherapy (such as ananti-PD-1 antibody including pembrolizumab and nivolumab, or ananti-PD-L1 antibody including atezolizumab, durvalumab, and avelumab),or a CAR-T therapy (such as tisagenlecleucel, axicabtagene ciloleucel).

Also provided herein is the use of one or more compounds of theinvention, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising one or more compounds of theinvention, for the preparation of a medicament for the treatment of theabove-referenced diseases or conditions.

In another embodiment, provided herein the compounds of the invention,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising one or more of the disclosed compounds are foruse in treating the above-referenced diseases or conditions.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims. Itshould be understood that all embodiments/features of the invention(compounds, pharmaceutical compositions, methods of make/use, etc)described herein, including any specific features described in theexamples and original claims, can combine with one another unless notapplicable or explicitly disclaimed.

DETAILED DESCRIPTION OF THE INVENTION

Exemplary compounds described herein include, but are not limited to,the following:

-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)    sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)    sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-2-(3-amino-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl-3,3-d2)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2H,4H-spiro[pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine-3,2′-[1,3]dithiolan]-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(6,7,8,9-tetrahydropyrrolo[3′,2′:5,6]pyrido[3,2-b]azepin-5(1H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl-3,3,4,4-d4)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3,4,5,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]diazepin-1(2H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-oxo-3,4,5,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]diazepin-1(2H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-(methylimino)-5-oxido-3,4,5,7-tetrahydro-5l4-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(2H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2′,3′-dihydrospiro[cyclopropane-1,4′-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin]-1′(7′H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1r,4r)-4-methoxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1s,4s)-4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-morpholinocyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(cyclopropylamino)cyclohexyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4,4-difluorocyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(2-morpholinoethoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-methoxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-ethyl-4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-morpholinocyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(cyclopropylamino)cyclohexyl)oxy)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4,4-difluorocyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-4-(methoxymethyl)-4-methyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-5-fluoro-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((5-nitro-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-3-yl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(7,8-dihydro-3H-imidazo[4′,5′:5,6]pyrido[2,3-b][1,4]oxazepin-9(6H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-methyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-(1,3-difluoropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-difluoro-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((5-(4-chlorophenyl)spiro[2.5]oct-5-en-6-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((7-(4-chlorophenyl)spiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-3′-fluoro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(4-((4,4-dimethyl-2-(pyridin-3-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-6-fluorobenzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-5-fluorobenzamide,-   4-(4-((4′-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-2-methylpiperazin-1-yl-2,3,3,5,5,6,6-d7)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   diethyl    ((2-(((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino)methyl)phosphonate,-   diethyl    (((3-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)propyl)(methyl)amino)methyl)phosphonate,-   2-(((2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)((pivaloyloxy)methoxy)phosphoryl)oxy)ethyl    pivalate,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-methyl-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-hydroxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   ((4-(((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)-1-oxidophosphinan-1-yl)oxy)methyl    pivalate,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-methyl-2-oxido-1,3,2-oxazaphosphinan-5-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(2-methyl-2-oxido-1,3,2-oxazaphosphinan-3-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-(dimethylphosphoryl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-(dimethylphosphoryl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-(((1,4-dioxaspiro[4.5]decan-8-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   N-((4-(((2-oxaspiro[3.5]nonan-7-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(3-oxooctahydro-7H-imidazo[1,5-d][1,4]diazepin-7-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(3-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-((2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3-hydroxy-3-methylbicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-((2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   2-((3R)-8-(2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetic    acid,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-thiopyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-(methylsulfonyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-((dimethyl(oxo)-λ6-sulfaneylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(4-((dimethyl(oxo)-λ6-sulfaneylidene)amino)piperidin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(tetrahydro-2H-pyran-4-yl)cyclopropyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(difluoromethoxy)benzyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxytetrahydrofuran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4,5-dihydroxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((2,3,4,5,6-pentahydroxycyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-3-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)picolinamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)nicotinamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-dimethyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-2-(3-amino-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5,5-dioxido-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methyl-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-cyano-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-hydroxy-3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2′H,4′H-spiro[cyclobutane-1,3′-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin]-1′(7′H)-yl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-dimethyl-4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(9-oxo-6,7,8,9-tetrahydropyrrolo[3′,2′:5,6]pyrido[3,2-b]azepin-5(1H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(5-(oxetan-3-yl)-3,4,5,7-tetrahydropyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]diazepin-1(2H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(2-oxo-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-imino-5-oxido-3,4,5,7-tetrahydro-5l4-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(2H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(5-methyl-5-oxido-3,4,7-trihydropyrrolo[3′,2′:5,6]pyrido[3,2-b][1,4]azaphosphepin-1(2H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3-fluorotetrahydro-2H-pyran-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((3-morpholinopropyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((4-(oxetan-3-yl)morpholin-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1s,4s)-4-methoxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1r,4r)-4-ethyl-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-morpholinocyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((1,4,4-trifluorocyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((3-fluorotetrahydro-2H-pyran-3-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(3-morpholinopropoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-methylmorpholin-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   (R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1s,4s)-4-methoxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r-4-ethyl-4-hydroxycyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1r,4r)-4-morpholinocyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((4-(methyl(oxetan-3-yl)amino)cyclohexyl)oxy)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((1,4,4-trifluorocyclohexyl)methoxy)phenyl)sulfonyl)benzamide,-   4-(4-((4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (Z)-4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-4-methoxy-4-methyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(54(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl    sulfonimidoyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-3-(S-(trifluoromethyl)sulfonimidoyl)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-[1,4]oxazepino[3,2-f]indol-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-isopropyl-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((9-(4-chlorophenyl)-3-(oxetan-3-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-bis(fluoromethyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-(1-(4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)cyclopropyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-3′,5,5-trimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((2-(1H-indol-5-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-3-fluorobenzamide,-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-6-fluorobenzamide,-   4-(4-((4′-chloro-5,5-bis(methyl-d3)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl-2,2,3,3,4,4-d6)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   ((2-(((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)methyl)morpholino)methyl)phosphonic    acid,-   diethyl    (2-((2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)(methyl)amino)ethyl)phosphonate,-   ethyl    P-(2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-N,N-dimethylphosphonamidate,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-(dimethylamino)-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-ethoxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-isopropoxy-1-oxidophosphinan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((1,2,3-trimethyl-2-oxido-1,3,2-diazaphosphinan-5-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(2-methyl-2-oxido-1,3,2-diazaphosphinan-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-(dimethylphosphoryl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(dimethylphosphoryl)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-(((1,4-dithiaspiro[4.5]decan-8-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   N-((4-((2-(6-azaspiro[2.5]octan-6-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(2-(oxetan-3-yl)octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(1-oxooctahydro-5H-pyrrolo[3,4-c]pyridin-5-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3-hydroxybicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   N-((4-(((3-amino-3-methylbicyclo[3.1.1]heptan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)amino)phenyl)sulfonyl)benzamide,-   2-((3S)-8-(2-((4-(N-(4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoyl)sulfamoyl)-2-nitrophenyl)amino)ethyl)-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl)acetic    acid,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   N-((4-((7-oxaspiro[3.5]nonan-2-yl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((1-(isopropylimino)-1-oxidohexahydro-1λ6-thiopyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-(S-methylsulfonimidoyl)morpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((4-((1-oxidotetrahydro-1λ6-thiophen-1-ylidene)amino)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((1-(4-((dimethyl(oxo)-λ6-sulfaneylidene)amino)piperidin-1-yl)propan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-cyanotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((2-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((1-(thiazol-2-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(difluoromethoxy)benzyl)amino)-3-nitrophenyl)sulfonyl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((3,5-dihydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((2,3,5-trihydroxytetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((3,4,5-trihydroxy-6-(((4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)methoxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide,-   4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide,-   (S)-6-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-4-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-3-yl)methyl)amino)phenyl)sulfonyl)nicotinamide,    or-   (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-6-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)nicotinamide.

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Diastereomeric compounds may be separated bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated using the same techniques or others known inthe art. Each of the asymmetric carbon atoms may be in the R or Sconfiguration, and both of these configurations are within the scope ofthe invention.

Compounds having one or more chiral centers can exist in variousstereoisomeric forms. Stereoisomers are compounds that differ only intheir spatial arrangement. Stereoisomers include all diastereomeric,enantiomeric, and epimeric forms as well as racemates and mixturesthereof.

The term “geometric isomer” refers to cyclic compounds having at leasttwo substituents, wherein the two substituents are both on the same sideof the ring (cis) or wherein the substituents are each on opposite sidesof the ring (trans). When a disclosed compound is named or depicted bystructure without indicating stereochemistry, it is understood that thename or the structure encompasses one or more of the possiblestereoisomers, or geometric isomers, or a mixture of the encompassedstereoisomers or geometric isomers.

When a geometric isomer is depicted by name or structure, it is to beunderstood that the named or depicted isomer exists to a greater degreethan another isomer, that is that the geometric isomeric purity of thenamed or depicted geometric isomer is greater than 50%, such as at least60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomericpurity is determined by dividing the weight of the named or depictedgeometric isomer in the mixture by the total weight of all of thegeometric isomers in the mixture.

Racemic mixture means 50% of one enantiomer and 50% of is correspondingenantiomer. When a compound with one chiral center is named or depictedwithout indicating the stereochemistry of the chiral center, it isunderstood that the name or structure encompasses both possibleenantiomeric forms (e.g., both enantiomerically-pure,enantiomerically-enriched or racemic) of the compound. When a compoundwith two or more chiral centers is named or depicted without indicatingthe stereochemistry of the chiral centers, it is understood that thename or structure encompasses all possible diasteriomeric forms (e.g.,diastereomerically pure, diastereomerically enriched and equimolarmixtures of one or more diastereomers (e.g., racemic mixtures) of thecompound.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well-known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers also can be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers is included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomericpurity in this case is determined by dividing the total weight in themixture of the stereoisomers encompassed by the name or structure by thetotal weight in the mixture of all of the stereoisomers.

A modified compound of any one of such compounds including amodification having an improved (e.g., enhanced, greater) pharmaceuticalsolubility, stability, bioavailability and/or therapeutic index ascompared to the unmodified compound is also contemplated. The examplesof modifications include but not limited to the prodrug derivatives, andthe deuterium-enriched compounds. For example:

-   -   Prodrug derivatives: prodrugs, upon administration to a subject,        will converted in vivo into active compounds of the present        invention [Nature Reviews of Drug Discovery, 2008, Volume 7, p        255]. It is noted that in many instances, the prodrugs        themselves also fall within the scope of the range of compounds        according to the present invention. The prodrugs of the        compounds of the present invention can be prepared by standard        organic reaction, for example, by reacting with a carbamylating        agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl        carbonate, or the like) or an acylating agent. Further examples        of methods and strategies of making prodrugs are described in        Bioorganic and Medicinal Chemistry Letters, 1994, Vol. 4, p.        1985.    -   Deuterium-enriched compounds: deuterium (D or ²H) is a stable,        non-radioactive isotope of hydrogen and has an atomic weight of        2.0144. Hydrogen naturally occurs as a mixture of the isotopes        ^(X)H (hydrogen or protium), D (²H or deuterium), and T (³H or        tritium). The natural abundance of deuterium is 0.015%. One of        ordinary skill in the art recognizes that in all chemical        compounds with a H atom, the H atom actually represents a        mixture of H and D, with about 0.015% being D. Thus, compounds        with a level of deuterium that has been enriched to be greater        than its natural abundance of 0.015%, should be considered        unnatural and, as a result, novel over their nonenriched        counterparts.

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, andsolvates. The invention encompasses any pharmaceutically acceptablesalts and solvates of any one of the above-described compounds andmodifications thereof. For example, it is within the scope of thepresent invention to convert the compounds of the present invention intoand use them in the form of their pharmaceutically acceptable saltsderived from various organic and inorganic acids and bases in accordancewith procedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids such as sulfate, nitrate, phosphate, etc.; and alkyl andmonoarylsulfonates such as ethanesulfonate, toluenesulfonate andbenzenesulfonate; and other organic acids and their corresponding saltssuch as acetate, tartrate, maleate, succinate, citrate, benzoate,salicylate and ascorbate. Further acid addition salts of the presentinvention include, but are not limited to: adipate, alginate, arginate,aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucicacid), galacturonate, glucoheptaoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate,lactate, lactobionate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, oxalate, oleate, pamoate, pectinate,persulfate, phenylacetate, 3-phenylpropionate, phosphonate andphthalate. It should be recognized that the free base forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free base forms for the purposes ofthe present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

In one aspect, a pharmaceutically acceptable salt is a hydrochloridesalt, hydrobromide salt, methanesulfonate, toluenesulfonate, acetate,fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate,nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxidesalt, calcium hydroxide salt, potassium hydroxide salt, tromethaminesalt, or mixtures thereof.

Compounds of the present invention that comprise tertiarynitrogen-containing groups may be quaternized with such agents as (C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di-(C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; alkyl halides, e.g., decyl, dodecyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; and aryl (C₁₋₄)alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such saltspermit the preparation of both water- and oil-soluble compounds of theinvention.

Amine oxides, also known as amine-N-oxide and N-oxide, of anti-canceragents with tertiary nitrogen atoms have been developed as prodrugs [MolCancer Therapy. 2004 March; 3(3):233-44]. Compounds of the presentinvention that comprise tertiary nitrogen atoms may be oxidized by suchagents as hydrogen peroxide (H₂O₂), Caro's acid or peracids likemeta-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.

The compounds disclosed therein are bcl-2 inhibitors. The pharmaceuticalcomposition of the present invention comprises one or more bcl-2inhibitors, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

“Pharmaceutically acceptable carrier” and “pharmaceutically acceptablediluent” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the compositions of the present disclosure withoutcausing a significant adverse toxicological effect on the subject.Non-limiting examples of pharmaceutically acceptable carriers and/ordiluents include water, NaCl, normal saline solutions, lactatedRinger's, normal sucrose, normal glucose, binders, fillers,disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions(such as Ringer's solution), alcohols, oils, gelatins, carbohydratessuch as lactose, amylose or starch, fatty acid esters,hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.Such preparations can be sterilized and, if desired, mixed withauxiliary agents such as lubricants, preservatives, stabilizers, wettingagents, emulsifiers, salts for influencing osmotic pressure, buffers,coloring, and/or aromatic substances and the like that do notdeleteriously react with or interfere with the activity of the compoundsprovided herein. One of ordinary skill in the art will recognize thatother pharmaceutical excipients are suitable for use with disclosedcompounds.

The pharmaceutical compositions of the present invention optionallyinclude one or more pharmaceutically acceptable carriers and/or diluentstherefor, such as lactose, starch, cellulose and dextrose. Otherexcipients, such as flavoring agents; sweeteners; and preservatives,such as methyl, ethyl, propyl and butyl parabens, can also be included.More complete listings of suitable excipients can be found in theHandbook of Pharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press(2005)). A person skilled in the art would know how to prepareformulations suitable for various types of administration routes.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington's Pharmaceutical Sciences (2003—20th edition) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19)published in 1999. The carriers, diluents and/or excipients are“acceptable” in the sense of being compatible with the other ingredientsof the pharmaceutical composition and not deleterious to the recipientthereof.

The pharmaceutical compositions of the present invention may furthercomprise other conventional pharmaceutically inactive agents. Any inertexcipient that is commonly used as a carrier or diluent may be used incompositions of the present invention, such as sugars, polyalcohols,soluble polymers, salts and lipids. Sugars and polyalcohols which may beemployed include, without limitation, lactose, sucrose, mannitol, andsorbitol. Illustrative of the soluble polymers which may be employed arepolyoxyethylene, poloxamers, polyvinylpyrrolidone, and dextran. Usefulsalts include, without limitation, sodium chloride, magnesium chloride,and calcium chloride. Lipids which may be employed include, withoutlimitation, fatty acids, glycerol fatty acid esters, glycolipids, andphospholipids.

In addition, the pharmaceutical compositions of the present inventionmay further comprise binders (e.g., acacia, cornstarch, gelatin,carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g.,cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellosesodium, crospovidone, guar gum, sodium starch glycolate, Primogel),buffers (e.g., tris-HCL, acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., glycerol, polyethyleneglycerol, cyclodextrins), a glidant (e.g., colloidal silicon dioxide),anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylatedhydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose,hydroxypropylmethyl cellulose), viscosity increasing agents (e.g.,carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweeteners (e.g., sucrose, aspartame, citric acid), flavoring agents(e.g., peppermint, methyl salicylate, or orange flavoring),preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants(e.g., stearic acid, magnesium stearate, polyethylene glycol, sodiumlauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate, methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In one embodiment, the pharmaceutical compositions are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

Additionally, the invention encompasses pharmaceutical compositionscomprising any solid or liquid physical form of the compound of theinvention. For example, the compounds can be in a crystalline form, inamorphous form, and have any particle size. The particles may bemicronized, or may be agglomerated, particulate granules, powders, oils,oily suspensions or any other form of solid or liquid physical form.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, pH adjustment and salt formation, using co-solvents,such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), using surfactants, suchas polysorbate 80, polysorbate 20 (1-10%), cremophor EL, Cremophor RH40,Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), SolutolHS15 (20-50%), Vitamin E TPGS, and d-α-tocopheryl PEG 1000 succinate(20-50%), using complexation such as HPβCD and SBEβCD (10-40%), andusing advanced approaches such as micelle, addition of a polymer,nanoparticle suspensions, and liposome formation.

A wide variety of administration methods may be used in conjunction withthe compounds of the present invention. Compounds of the presentinvention may be administered or coadministered orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compoundsaccording to the invention may also be administered or coadministered inslow release dosage forms. Compounds may be in gaseous, liquid,semi-liquid or solid form, formulated in a manner suitable for the routeof administration to be used. For oral administration, suitable solidoral formulations include tablets, capsules, pills, granules, pellets,sachets and effervescent, powders, and the like. Suitable liquid oralformulations include solutions, suspensions, dispersions, emulsions,oils and the like. For parenteral administration, reconstitution of alyophilized powder is typically used.

As used herein, “acyl” means a carbonyl containing substituentrepresented by the formula —C(O)—R in which R is H, alkyl, a carbocycle,a heterocycle, carbocycle-substituted alkyl or heterocycle-substitutedalkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are asdefined herein. Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g.benzoyl), and heteroaroyl.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one or more double or triple bonds.

The term “alkyl” refers to a straight or branched hydrocarbon containing1-20 carbon atoms (e.g., C₁-C₁₀, C₁-C₆). Examples of alkyl include, butare not limited to, methyl, methylene, ethyl, ethylene, n-propyl,i-propyl, n-butyl, i-butyl, and t-butyl. Preferably, the alkyl group hasone to ten carbon atoms. More preferably, the alkyl group has one tofour carbon atoms.

The term “alkenyl” refers to a straight or branched hydrocarboncontaining 2-20 carbon atoms (e.g., C₂-C₁₀, C₂-C₆) and one or moredouble bonds. Examples of alkenyl include, but are not limited to,ethenyl, propenyl, and allyl. Preferably, the alkylene group has two toten carbon atoms. More preferably, the alkylene group has two to fourcarbon atoms.

The term “alkynyl” refers to a straight or branched hydrocarboncontaining 2-20 carbon atoms (e.g., C₂-C₁₀, C₂-C₆) and one or moretriple bonds. Examples of alkynyl include, but are not limited to,ethynyl, 1-propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl.Preferably, the alkynyl group has two to ten carbon atoms. Morepreferably, the alkynyl group has two to four carbon atoms.

The term “alkylamino” refers to an —N(R)-alkyl in which R can be H,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, or heteroaryl.

“Alkoxy” means an oxygen moiety having a further alkyl substituent.

“Alkoxycarbonyl” means an alkoxy group attached to a carbonyl group.

“Oxoalkyl” means an alkyl, further substituted with a carbonyl group.The carbonyl group may be an aldehyde, ketone, ester, amide, acid oracid chloride.

The term “cycloalkyl” refers to a saturated hydrocarbon ring systemhaving 3 to 30 carbon atoms (e.g., C₃-C₁₂, C₃-C₈, C₃-C₆). Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term“cycloalkenyl” refers to a non-aromatic hydrocarbon ring system having 3to 30 carbons (e.g., C₃-C₁₂) and one or more double bonds. Examplesinclude cyclopentenyl, cyclohexenyl, and cycloheptenyl.

The term “heterocycloalkyl” refers to a saturated or unsaturatednonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14membered tricyclic ring system having 1 to 4 heteroatoms (such as O, N,S, B, P, Si, or Se), which may be the same or different. Examples ofheterocycloalkyl groups include, but are not limited to, piperazinyl,pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

The term “heterocycloalkenyl” refers to a nonaromatic 5-8 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having one or more heteroatoms (such as O, N, S, P, B, Si, or Se)and one or more double bonds.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic,14-carbon tricyclic aromatic ring system. Examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, and anthracenyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system havingone or more heteroatoms (such as O, N, S, P, or Se). Examples ofheteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl,pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.

Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, alkylamino, aryl, and heteroaryl mentioned aboveinclude both substituted and unsubstituted moieties. Possiblesubstituents on alkylamino, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl, and heteroaryl include, but are not limitedto, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ cycloalkenyl, C₁-C₂₀ heterocycloalkyl, C₁-C₂₀ heterocycloalkenyl,C₁-C₁₀ alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀alkylamino, arylamino, hydroxy, halo, oxo (O═), thioxo (S═), thio,silyl, C₁-C₁₀ alkylthio, arylthio, C₁-C₁₀ alkylsulfonyl, arylsulfonyl,acylamino, aminoacyl, aminothioacyl, amidino, mercapto, amido,thioureido, thiocyanato, sulfonamido, guanidine, ureido, cyano, nitro,acyl, thioacyl, acyloxy, carbamido, carbamyl, carboxyl, and carboxylicester. On the other hand, possible substituents on alkyl, alkenyl, oralkynyl include all of the above-recited substituents except C₁-C₁₀alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,aryl, and heteroaryl can also be fused with each other.

“Amino” means a nitrogen moiety having two further substituents whereeach substituent has a hydrogen or carbon atom alpha bonded to thenitrogen. Unless indicated otherwise, the compounds of the inventioncontaining amino moieties may include protected derivatives thereof.Suitable protecting groups for amino moieties include acetyl,tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp2 hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (see Heteroaryl).

“Carbamoyl” means the radical —OC(O)NR_(a)R_(b) where R_(a) and R_(b)are each independently two further substituents where a hydrogen orcarbon atom is alpha to the nitrogen. It is noted that carbamoylmoieties may include protected derivatives thereof. Examples of suitableprotecting groups for carbamoyl moieties include acetyl,tert-butoxycarbonyl, benzyloxycarbonyl, and the like. It is noted thatboth the unprotected and protected derivatives fall within the scope ofthe invention.

“Carbonyl” means the radical —C(O)—. It is noted that the carbonylradical may be further substituted with a variety of substituents toform different carbonyl groups including acids, acid halides, amides,esters, and ketones.

“Carboxy” means the radical —C(O)O—. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Formyl” means the radical —CH═O.

“Formimino” means the radical —HC═NH.

“Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl”, as an isolated group or part of a largergroup, means “alkyl” substituted by one or more “halo” atoms, as suchterms are defined in this Application. Halo-substituted alkyl includeshaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like.

“Hydroxy” means the radical —OH.

“Imine derivative” means a derivative comprising the moiety —C(═NR)—,wherein R comprises a hydrogen or carbon atom alpha to the nitrogen.

“Isomers” mean any compound having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.”

“Nitro” means the radical —NO₂.

“Protected derivatives” means derivatives of compounds in which areactive site are blocked with protecting groups. Protected derivativesare useful in the preparation of pharmaceuticals or in themselves may beactive as inhibitors. A comprehensive list of suitable protecting groupscan be found in T. W. Greene, Protecting Groups in Organic Synthesis,3rd edition, Wiley & Sons, 1999.

The term “substituted” means that an atom or group of atoms has replacedhydrogen as the substituent attached to another group. For aryl andheteroaryl groups, the term “substituted” refers to any level ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.The term “unsubstituted” means that a given moiety may consist of onlyhydrogen substituents through available valencies (unsubstituted).

If a functional group is described as being “optionally substituted,”the function group may be either (1) not substituted, or (2)substituted. If a carbon of a functional group is described as beingoptionally substituted with one or more of a list of substituents, oneor more of the hydrogen atoms on the carbon (to the extent there areany) may separately and/or together be replaced with an independentlyselected optional substituent.

“Sulfide” means —S—R wherein R is H, alkyl, carbocycle, heterocycle,carbocycloalkyl or heterocycloalkyl. Particular sulfide groups aremercapto, alkylsulfide, for example methylsulfide (—S-Me); arylsulfide,e.g., phenylsulfide; aralkylsulfide, e.g., benzylsulfide.

“Sulfinyl” means the radical —S(O)—. It is noted that the sulfinylradical may be further substituted with a variety of substituents toform different sulfinyl groups including sulfinic acids, sulfinamides,sulfinyl esters, and sulfoxides.

“Sulfonyl” means the radical —S(O)(O)—. It is noted that the sulfonylradical may be further substituted with a variety of substituents toform different sulfonyl groups including sulfonic acids, sulfonamides,sulfonate esters, and sulfones.

“Thiocarbonyl” means the radical —C(S)—. It is noted that thethiocarbonyl radical may be further substituted with a variety ofsubstituents to form different thiocarbonyl groups including thioacids,thioamides, thioesters, and thioketones.

“Animal” includes humans, non-human mammals (e.g., non-human primates,rodents, mice, rats, hamsters, dogs, cats, rabbits, cattle, horses,sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds,and the like).

“Bioavailability” as used herein is the fraction or percentage of anadministered dose of a drug or pharmaceutical composition that reachesthe systemic circulation intact. In general, when a medication isadministered intravenously, its bioavailability is 100%. However, when amedication is administered via other routes (e.g., orally), itsbioavailability decreases (e.g., due to incomplete absorption andfirst-pass metabolism). Methods to improve the bioavailability includeprodrug approach, salt synthesis, particle size reduction, complexation,change in physical form, solid dispersions, spray drying, and hot-meltextrusion.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means organic or inorganic salts ofcompounds of the present invention which are pharmaceuticallyacceptable, as defined above, and which possess the desiredpharmacological activity. Such salts include acid addition salts formedwith inorganic acids, or with organic acids. Pharmaceutically acceptablesalts also include base addition salts which may be formed when acidicprotons present are capable of reacting with inorganic or organic bases.Exemplary salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucuronate,saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate,”ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g.,sodium and potassium) salts, alkaline earth metal (e.g., magnesium)salts, and ammonium salts. A pharmaceutically acceptable salt mayinvolve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counter ion.

“Pharmacophore,” as defined by The International Union of Pure andApplied Chemistry, is an ensemble of steric and electronic features thatis necessary to ensure the optimal supramolecular interactions with aspecific biological target and to trigger (or block) its biologicalresponse. For example, Camptothecin is the pharmacophore of the wellknown drug topotecan and irinotecan. Mechlorethamine is thepharmacophore of a list of widely used nitrogen mustard drugs likeMelphalan, Cyclophosphamide, Bendamustine, and so on.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an active pharmaceutical according to the present invention. Forexample, an inhibitor comprising a hydroxyl group may be administered asan ester that is converted by hydrolysis in vivo to the hydroxylcompound.

“Stability” in general refers to the length of time a drug retains itsproperties without loss of potency. Sometimes this is referred to asshelf life. Factors affecting drug stability include, among otherthings, the chemical structure of the drug, impurity in the formulation,pH, moisture content, as well as environmental factors such astemperature, oxidization, light, and relative humidity. Stability can beimproved by providing suitable chemical and/or crystal modifications(e.g., surface modifications that can change hydration kinetics;different crystals that can have different properties), excipients(e.g., anything other than the active substance in the dosage form),packaging conditions, storage conditions, etc.

“Therapeutically effective amount” of a composition described herein ismeant an amount of the composition which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of thecomposition described above may range from about 0.1 mg/kg to about 500mg/kg, preferably from about 0.2 to about 50 mg/kg. Effective doses willalso vary depending on route of administration, as well as thepossibility of co-usage with other agents. It will be understood,however, that the total daily usage of the compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

As used herein, the term “treating” refers to administering a compoundto a subject that has a neoplastic or immune disorder, or has a symptomof or a predisposition toward it, with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve, or affect thedisorder, the symptoms of or the predisposition toward the disorder. Theterm “an effective amount” refers to the amount of the active agent thatis required to confer the intended therapeutic effect in the subject.Effective amounts may vary, as recognized by those skilled in the art,depending on route of administration, excipient usage, and thepossibility of co-usage with other agents.

A “subject” refers to a human and a non-human animal. Examples of anon-human animal include all vertebrates, e.g., mammals, such asnon-human primates (particularly higher primates), dog, rodent (e.g.,mouse or rat), guinea pig, cat, and non-mammals, such as birds,amphibians, reptiles, etc. In a preferred embodiment, the subject is ahuman. In another embodiment, the subject is an experimental animal oranimal suitable as a disease model.

“Combination therapy” includes the administration of the subjectcompounds of the present invention in further combination with otherbiologically active ingredients (such as, but not limited to, a secondand different antineoplastic agent) and non-drug therapies (such as, butnot limited to, surgery or radiation treatment). For instance, thecompounds of the invention can be used in combination with otherpharmaceutically active compounds, or non-drug therapies, preferablycompounds that are able to enhance the effect of the compounds of theinvention. The compounds of the invention can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other therapies. In general, a combination therapyenvisions administration of two or more drugs/treatments during a singlecycle or course of therapy.

In one embodiment, the compounds of the invention are administered incombination with one or more of traditional chemotherapeutic agents. Thetraditional chemotherapeutic agents encompass a wide range oftherapeutic treatments in the field of oncology. These agents areadministered at various stages of the disease for the purposes ofshrinking tumors, destroying remaining cancer cells left over aftersurgery, inducing remission, maintaining remission and/or alleviatingsymptoms relating to the cancer or its treatment. Examples of suchagents include, but are not limited to, alkylating agents such asNitrogen Mustards (e.g., Bendamustine, Cyclophosphamide, Melphalan,Chlorambucil, Isofosfamide), Nitrosureas (e.g., Carmustine, Lomustineand Streptozocin), ethylenimines (e.g., thiotepa, hexamethylmelanine),Alkylsulfonates (e.g., Busulfan), Hydrazines and Triazines (e.g.,Altretamine, Procarbazine, Dacarbazine and Temozolomide), and platinumbased agents (e.g., Carboplatin, Cisplatin, and Oxaliplatin); plantalkaloids such as Podophyllotoxins (e.g., Etoposide and Tenisopide),Taxanes (e.g., Paclitaxel and Docetaxel), Vinca alkaloids (e.g.,Vincristine, Vinblastine and Vinorelbine); anti-tumor antibiotics suchas Chromomycins (e.g., Dactinomycin and Plicamycin), Anthracyclines(e.g., Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, andIdarubicin), and miscellaneous antibiotics such as Mitomycin andBleomycin; anti-metabolites such as folic acid antagonists (e.g.,Methotrexate), pyrimidine antagonists (e.g., 5-Fluorouracil, Foxuridine,Cytarabine, Capecitabine, and Gemcitabine), purine antagonists (e.g.,6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors(e.g., Cladribine, Fludarabine, Nelarabine and Pentostatin);topoisomerase inhibitors such as topoisomerase I inhibitors (Topotecan,Irinotecan), topoisomerase II inhibitors (e.g., Amsacrine, Etoposide,Etoposide phosphate, Teniposide), and miscellaneous anti-neoplasticssuch as ribonucleotide reductase inhibitors (Hydroxyurea),adrenocortical steroid inhibitor (Mitotane), anti-microtubule agents(Estramustine), and retinoids (Bexarotene, Isotretinoin, Tretinoin(ATRA).

In one aspect of the invention, the compounds may be administered incombination with one or more targeted anti-cancer agents that modulateprotein kinases involved in various disease states. Examples of suchkinases may include, but are not limited ABL1, ABL2/ARG, ACK1, AKT1,AKT2, AKT3, ALK, ALK1/ACVRL1, ALK2/ACVR1, ALK4/ACVR1B, ALK5/TGFBR1,ALK6/BMPR1B, AMPK(A1/B1/G1), AMPK(A1/B1/G2), AMPK(A1/B1/G3),AMPK(A1/B2/G1), AMPK(A2/B1/G1), AMPK(A2/B2/G1), AMPK(A2/B2/G2), ARAF,ARK5/NUAK1, ASK1/MAP3K5, ATM, Aurora A, Aurora B, Aurora C, AXL, BLK,BMPR2, BMX/ETK, BRAF, BRK, BRSK1, BRSK2, BTK, CAMK1a, CAMK1b, CAMK1d,CAMK1g, CAMKIIa, CAMKIIb, CAMKIId, CAMKIIg, CAMK4, CAMKK1, CAMKK2,CDC7-DBF4, CDK1-cyclin A, CDK1-cyclin B, CDK1-cyclin E, CDK2-cyclin A,CDK2-cyclin A1, CDK2-cyclin E, CDK3-cyclin E, CDK4-cyclin D1,CDK4-cyclin D3, CDK5-p25, CDK5-p35, CDK6-cyclin D1, CDK6-cyclin D3,CDK7-cyclin H, CDK9-cyclin K, CDK9-cyclin T1, CHK1, CHK2, CK1a1, CK1d,CK1epsilon, CK1g1, CK1g2, CK1g3, CK2a, CK2a2, c-KIT, CLK1, CLK2, CLK3,CLK4, c-MER, c-MET, COT1/MAP3K8, CSK, c-SRC, CSF1R, CTK/MATK, DAPK1,DAPK2, DCAMKL1, DCAMKL2, DDR1, DDR2, DLK/MAP3K12, DMPK, DMPK2/CDC42BPG,DNA-PK, DRAK1/STK17A, DYRK1/DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K,EGFR, EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4/GCN2, EPHA1, EPHA2, EPHA3,EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4,ERBB2/HER2, ERBB4/HER4, ERK1/MAPK3, ERK2/MAPK1, ERK5/MAPK7, FAK/PTK2,FER, FES/FPS, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1/VEGFR1, FLT3,FLT4/VEGFR3, FMS, FRK/PTK5, FYN, GCK/MAP4K2, GRK1, GRK2, GRK3, GRK4,GRK5, GRK6, GRK7, GSK3a, GSK3b, Haspin, HCK, HGK/MAP4K4, HIPK1, HIPK2,HIPK3, HIPK4, HPK1/MAP4K1, IGF1R, IKKa/CHUK, IKKb/IKBKB, IKKe/IKBKE, IR,IRAK1, IRAK4, IRR/INSRR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3,KDR/VEGFR2, KHS/MAP4K5, LATS1, LATS2, LCK, LCK2/ICK, LKB1, LIMK1,LOK/STK10, LRRK2, LYN, LYNB, MAPKAPK2, MAPKAPK3, MAPKAPK5/PRAK, MARK1,MARK2/PAR-1Ba, MARK3, MARK4, MEK1, MEK2, MEKK1, MEKK2, MEKK3, MELK,MINK/MINK1, MKK4, MKK6, MLCK/MYLK, MLCK2/MYLK2, MLK1/MAP3K9,MLK2/MAP3K10, MLK3/MAP3K11, MNK1, MNK2, MRCKa/, CDC42BPA, MRCKb/,CDC42BPB, MSK1/RPS6KA5, MSK2/RPS6KA4, MSSK1/STK23, MST1/STK4, MST2/STK3,MST3/STK24, MST4, mTOR/FRAP1, MUSK, MYLK3, MYO3b, NEK1, NEK2, NEK3,NEK4, NEK6, NEK7, NEK9, NEK11, NIK/MAP3K14, NLK, OSR1/OXSR1,P38a/MAPK14, P38b/MAPK11, P38d/MAPK13, P38g/MAPK12, P70S6K/RPS6KB1,p70S6Kb/, RPS6KB2, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PASK, PBK/TOPK,PDGFRa, PDGFRb, PDK1/PDPK1, PDK1/PDHK1, PDK2/PDHK2, PDK3/PDHK3,PDK4/PDHK4, PHKg1, PHKg2, PI3Ka, (p110a/p85a), PI3Kb, (p110b/p85a),PI3Kd, (p110d/p85a), PI3Kg(p120g), PIM1, PIM2, PIM3, PKA, PKAcb, PKAcg,PKCa, PKCb1, PKCb2, PKCd, PKCepsilon, PKCeta, PKCg, PKCiota,PKCmu/PRKD1, PKCnu/PRKD3, PKCtheta, PKCzeta, PKD2/PRKD2, PKG1a, PKG1b,PKG2/PRKG2, PKN1/PRK1, PKN2/PRK2, PKN3/PRK3, PLK1, PLK2, PLK3, PLK4/SAK,PRKX, PYK2, RAF1, RET, RIPK2, RIPK3, RIPK5, ROCK1, ROCK2, RON/MST1R,ROS/ROS1, RSK1, RSK2, RSK3, RSK4, SGK1, SGK2, SGK3/SGKL, SIK1, SIK2,SLK/STK2, SNARK/NUAK2, SRMS, SSTK/TSSK6, STK16, STK22D/TSSK1,STK25/YSK1, STK32b/YANK2, STK32c/YANK3, STK33, STK38/NDR1, STK38L/NDR2,STK39/STLK3, SRPK1, SRPK2, SYK, TAK1, TAOK1, TAOK2/TAO1, TAOK3/JIK,TBK1, TEC, TESK1, TGFBR2, TIE2/TEK, TLK1, TLK2, TNIK, TNK1, TRKA, TRKB,TRKC, TRPM7/CHAK1, TSSK2, TSSK3/STK22C, TTBK1, TTBK2, TTK, TXK,TYK1/LTK, TYK2, TYRO3/SKY, ULK1, ULK2, ULK3, VRK1, VRK2, WEE1, WNK1,WNK2, WNK3, YES/YES1, ZAK/MLTK, ZAP70, ZIPK/DAPK3, KINASE, MUTANTS,ABL1(E255K), ABL1(F317I), ABL1(G250E), ABL1(H396P), ABL1(M351T),ABL1(Q252H), ABL1(T315I), ABL1(Y253F), ALK (C1156Y), ALK(L1196M), ALK(F1174L), ALK (R1275Q), BRAF(V599E), BTK(E41K), CHK2(I157T),c-Kit(A829P), c-KIT(D816H), c-KIT(D816V), c-Kit(D820E), c-Kit(N822K),C-Kit (T670I), c-Kit(V559D), c-Kit(V559D/V654A), c-Kit(V559D/T670I),C-Kit (V560G), c-KIT(V654A), C-MET(D1228H), C-MET(D1228N),C-MET(F1200I), c-MET(M1250T), C-MET(Y1230A), C-MET(Y1230C),C-MET(Y1230D), C-MET(Y1230H), c-Src(T341M), EGFR(G719C), EGFR(G719S),EGFR(L858R), EGFR(L861Q), EGFR(T790M), EGFR, (L858R,T790M),EGFR(d746-750/T790M), EGFR(d746-750), EGFR(d747-749/A750P),EGFR(d747-752/P753S), EGFR(d752-759), FGFR1(V561M), FGFR2(N549H),FGFR3(G697C), FGFR3(K650E), FGFR3(K650M), FGFR4(N535K), FGFR4(V550E),FGFR4(V550L), FLT3(D835Y), FLT3(ITD), JAK2 (V617F), LRRK2 (G2019S),LRRK2 (12020T), LRRK2 (R1441C), p38a(T106M), PDGFRa(D842V),PDGFRa(T6741), PDGFRa(V561D), RET(E762Q), RET(G691S), RET(M918T),RET(R749T), RET(R813Q), RET(V804L), RET(V804M), RET(Y791F), TIF2(R849W),TIF2(Y897S), and TIF2(Y1108F).

In another aspect of the invention, the subject compounds may beadministered in combination with one or more targeted anti-cancer agentsthat modulate non-kinase biological targets, pathway, or processes. Suchtargets pathways, or processes include but not limited to heat shockproteins (e.g. HSP90), poly-ADP (adenosine diphosphate)-ribosepolymerase (PARP), hypoxia-inducible factors(HIF), proteasome,Wnt/Hedgehog/Notch signaling proteins, TNF-alpha, matrixmetalloproteinase, farnesyl transferase, apoptosis pathway (e.g Bcl-xL,Bcl-2, Bcl-w), histone deacetylases (HDAC), histone acetyltransferases(HAT), and methyltransferase (e.g histone lysine methyltransferases,histone arginine methyltransferase, DNA methyltransferase, etc), andother immunotherapies (e.g anti-PD1, anti-PDL1, anti-CTLA4, CAR-T, IDO,A2A antagonist etc).

In another aspect of the invention, the compounds of the invention areadministered in combination with one or more of other anti-cancer agentsthat include, but are not limited to, gene therapy, RNAi cancer therapy,chemoprotective agents (e.g., amfostine, mesna, and dexrazoxane),antibody conjugate (e.g brentuximab vedotin, ibritumomab tioxetan),cancer immunotherapy such as Interleukin-2, cancer vaccines (e.g.,sipuleucel-T) or monoclonal antibodies (e.g., Bevacizumab, Alemtuzumab,Rituximab, Trastuzumab, etc).

In another aspect of the invention, the subject compounds areadministered in combination with radiation therapy or surgeries.Radiation is commonly delivered internally (implantation of radioactivematerial near cancer site) or externally from a machine that employsphoton (x-ray or gamma-ray) or particle radiation. Where the combinationtherapy further comprises radiation treatment, the radiation treatmentmay be conducted at any suitable time so long as a beneficial effectfrom the co-action of the combination of the therapeutic agents andradiation treatment is achieved. For example, in appropriate cases, thebeneficial effect is still achieved when the radiation treatment istemporally removed from the administration of the therapeutic agents,perhaps by days or even weeks.

In certain embodiments, the compounds of the invention are administeredin combination with one or more of radiation therapy, surgery, oranti-cancer agents that include, but are not limited to, DNA damagingagents, anti-metabolites, topoisomerase inhibitors, anti-microtubuleagents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARPinhibitors, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30,CD33, etc.

In certain embodiments, the compounds of the invention are administeredin combination with one or more of abarelix, abiraterone acetate,aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase,bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin,bortezombi, brentuximab vedotin, busulfan, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,clomifene, crizotinib, cyclophosphamide, dasatinib, daunorubicinliposomal, decitabine, degarelix, denileukin diftitox, denileukindiftitox, denosumab, docetaxel, doxorubicin, doxorubicin liposomal,epirubicin, eribulin mesylate, erlotinib, estramustine, etoposidephosphate, everolimus, exemestane, fludarabine, fluorouracil,fotemustine, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin,goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,ipilimumab, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine,melphalan, methotrexate, mitomycin C, mitoxantrone, nelarabine,nilotinib, oxaliplatin, paclitaxel, paclitaxel protein-bound particle,pamidronate, panitumumab, pegaspargase, peginterferon alfa-2b,pemetrexed disodium, pentostatin, raloxifene, rituximab, sorafenib,streptozocin, sunitinib maleate, tamoxifen, temsirolimus, teniposide,thalidomide, toremifene, tositumomab, trastuzumab, tretinoin,uramustine, vandetanib, vemurafenib, vinorelbine, zoledronate,pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, astisagenlecleucel, axicabtagene ciloleucel, radiation therapy, orsurgery.

The invention further provides methods for the prevention or treatmentof a neoplastic disease or autoimmune disease. In one embodiment, theinvention relates to a method of treating a neoplastic disease orautoimmune disease, in a subject in need of treatment comprisingadministering to said subject a therapeutically effective amount of acompound of the invention. In one embodiment, the invention furtherprovides for the use of a compound of the invention in the manufactureof a medicament for halting or decreasing a neoplastic disease orautoimmune disease.

In certain embodiments, the neoplastic disease is a lung cancer, headand neck cancer, central nervous system cancer, prostate cancer,testicular cancer, colorectal cancer, pancreatic cancer, liver cancer,stomach cancer, biliary tract cancer, esophageal cancer,gastrointestinal stromal tumor, breast cancer, cervical cancer, ovariancancer, uterine cancer, leukemia, lymphomas, multiple myeloma, melanoma,basal cell carcinoma, squamous cell carcinoma, bladder cancer, renalcancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome, ormyeloproliferative disease.

The autoimmune diseases that can be affected using compounds andcompositions according to the invention include, but are not limited toallergy, Alzheimer's disease, acute disseminated encephalomyelitis,Addison's disease, ankylosing spondylitis, antiphospholipid antibodysyndrome, asthma, atherosclerosis, autoimmune hemolytic anemia,autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis,autoimmune inner ear disease, bullous pemphigoid, coeliac disease,chagas disease, chronic obstructive pulmonary disease, chronicIdiopathic thrombocytopenic purpura (ITP), churg-strauss syndrome,Crohn's disease, dermatomyositis, diabetes mellitus type 1,endometriosis, Goodpasture's syndrome (and associated glomerulonephritisand pulmonary hemorrhage), graves' disease, guillain-barré syndrome,hashimoto's disease, hidradenitis suppurativa, idiopathicthrombocytopenic purpura, interstitial cystitis, irritable bowelsyndrome, lupus erythematosus, morphea, multiple sclerosis, myastheniagravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigusvulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis,psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia,septic shock, scleroderma, Sjogren's disease, systemic lupuserythematosus (and associated glomerulonephritis), temporal arteritis,tissue graft rejection and hyperacute rejection of transplanted organs,vasculitis (ANCA-associated and other vasculitides), vitiligo, andwegener's granulomatosis.

It should be understood that the invention is not limited to theparticular embodiments shown and described herein, but that variouschanges and modifications may be made without departing from the spiritand scope of the invention as defined by the claims.

The compounds according to the present invention may be synthesizedaccording to a variety of schemes. Necessary starting materials may beobtained by standard procedures of organic chemistry. The compounds andprocesses of the present invention will be better understood inconnection with the following representative synthetic schemes andexamples, which are intended as an illustration only and not limiting ofthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

A typical approach to synthesize of the intermediate

is described in Scheme 1 below: R₁, R₂, m, and n, in general Scheme 1are the same as those described in the Summary section above.

In Scheme 1, the appropriate ketone starting material 1-1 can react withtribromophosphine to form the aldehyde intermediate 1-2, which cancouple with Boc-protected piperazine to form the intermediate 1-3. Afterthat, 1-3 will couple with appropriate phenylboronic acid via a Suzukireaction to form intermediate 1-4, followed by a de-boc process to yieldkey intermediate 1-5.

A typical approach to synthesize of the intermediate

in which R₅ is NO₂ is described in Scheme 2 below. R₄, R₅, L, and R₆, ingeneral Scheme 2 are the same as those described in the Summary sectionabove.

In Scheme 2, the starting material 2-1 reacts with appropriate alcoholor amine will yield 2-2.

A typical approach to synthesize of

is described in Scheme 4 below.

In Scheme 4, Protection of free NH of the commercially availablestarting material 3-6 yields 3-7 which can react with3,3-diethoxypropan-1-ol in the presence of a base to form the alkoxideintermediate 4-2. Subsequent Buckwald coupling with NH₂Boc affordsintermediate 4-3, which can be cyclized into tricyclic intermediate 4-4in tandem reactions: deprotection of Boc group, 7-member cyclic imineformation, and reduction.

A typical approach to synthesize of

in which Z₂, R₉, and k are the same as those described in the Summarysection above is described in Scheme 4-2 (Method A), 4-3 (Method B), 4-4(Method C) below.Method A

In Scheme 4-2, the substitution reaction of intermediate 3-1-2 (which issynthesized from 3-1-1 in the Scheme 3) affords the alkoxideintermediate 4-2-1. Subsequent Buchwald or Ullmann coupling with NH₂Bocaffords intermediate 4-2-2, which can be cyclized into tricyclicintermediate 4-2-3 in one-pot tandem reactions: deprotection of Bocgroup, 7-member cyclic imine formation, and reduction of imine.

Method B

In Scheme 4-3, 3-1-2 is converted into the alkoxide intermediate 4-3-1.Subsequent Buchwald or Ullmann reaction ring closure affordsintermediate 4-3-2, and following by deprotection of Ts group producesintermediate 4-3-3.

Method C

In Scheme 4-4, 3-1-2 is converted into the alkoxide intermediate 4-4-1.Subsequent Buchwald coupling or Ullmann reaction with NH₂-Ts affordsintermediate 4-4-2. And following by Mitsunobu ring closure of 4-4-2gives intermediate 4-4-3. Finally, deprotection of Ts group producesintermediate 4-4-4.

A typical approach to synthesize of

in which Z₂, R₉, and k are the same as those described in the Summarysection above is described in Scheme 4-5 (Method A), 4-6 (Method B), 4-7(Method B), below.Method A

In Scheme 4-5, the substitution reaction of intermediate 3-1-2 (which issynthesized from 3-1-1 in the Scheme 3) affords intermediate 4-5-1.Subsequent Buchwald or Ullmann coupling with NH₂Boc affords intermediate4-5-2, which can be cyclized into tricyclic intermediate 4-5-3 inone-pot tandem reactions: deprotection of Boc group, 7-member cyclicimine formation, and reduction.

Method B

In Scheme 4-6, 3-1-2 is converted into the intermediate 4-6-1.Subsequent Buchwald or Ullmann reaction ring closure affordsintermediate 4-6-2, and following by deprotection of Ts group producesintermediate 4-6-3.

Method C

In Scheme 4-7, 3-1-2 is converted into the intermediate 4-7-1 vianucleophilic aromatic substitution. Reduction of ester 4-7-1 (R=Me, Et)forms intermediate 4-7-2. Subsequent Buchwald or Ullmann coupling withNH₂-Ts affords intermediate 4-7-3, which undergoes via Mitsunobu ringclosure to form 4-7-4, and following by deprotection of Ts groupproduces intermediate 4-7-5.

A typical approach to synthesize of

in which Z₂, R₉, and k are the same as those described in the Summarysection above is described in Scheme 4-8 below.

In Scheme 4-8, the thioether N-oxidation of 4-8-1 (which is synthesizedfrom Scheme 4-5, 4-6, 4-7) reacts with m-CPBA to form intermediate4-8-2.

The intermediates of

in which Z₂, R₉, and k are the same as those described in the Summarysection above can be made by routes similar to Scheme 4, Scheme 4-2,Scheme 4-3, Scheme 4-4, Scheme 4-5, Scheme 4-6, Scheme 4-8.

Other intermediates of

in which Q is a 7 membered ring, R₇, R₈, R₉, Y, W, W₁, and k are thesame as those described in the Summary section above can be made byroutes similar to Scheme 4, Scheme 4-2, Scheme 4-3, Scheme 4-4, Scheme4-5, Scheme 4-6, Scheme 4-7, Scheme 4-8.

A typical approach to synthesize of Formula (D) compounds in which Z₂ isO is described in Scheme II:

In Scheme II, the intermediate 1-5 undergoes nucleophilic aromaticsubstitution with selected p-fluoro-2-bromo-benzoate to give II-2.Buckwald coupling of II-2 with appropriate amine intermediate yieldsII-3. II-3 is deprotected sequentially with TFA to remove SEM group andNaOH to remove ester group, producing free carboxylic acid intermediateII-5. Coupling of II-5 with 2-2 affords final product with Formula (D).

The compound of Formula (D) with different Z can be prepared by themethod similar to the General Scheme II by using appropriate staringmaterials and intermediates.

The compound of Formula (C), (B), and (A) can be prepared by the methodsimilar to the General Scheme II by using appropriate staring materialsand intermediates.

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Where NMR data are presented, ¹H spectra were obtained on XL400 (400MHz) and are reported as ppm down field from Me₄Si with number ofprotons, multiplicities, and coupling constants in Hertz indicatedparenthetically. Where HPLC data are presented, analyses were performedusing an Agilent 1100 system. Where LC/MS data are presented, analyseswere performed using an Applied Biosystems API-100 mass spectrometer andShimadzu SCL-10A LC column:

Example 1-1 Preparation of1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine

Synthesis of 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2: Asolution of anhydrous chloroform (57 ml) and anhydrousN,N-dimethylformamide (9 mL) were cooled to ˜3° C. (internaltemperature) under nitrogen before phosphorus tribromide (10 mL, 0.1mol) was introduced dropwise at a rate so that the reaction wasmaintained at ˜3° C. After the addition was complete the reaction wasallowed to warm slowly to ˜10° C. and then the temperature was raised to70° C. where it was maintained for 30 min. The reaction was cooled to rtand 3,3-dimethylcyclohexanone 1 (5 g, 0.04 mol) was added slowly over 20min. After the addition was complete the reaction was warmed to 70° C.and it was stirred for 1.5 h. The mixture was then cooled to 0° C. and asolution of 4M sodium acetate (53 ml) was added slowly. The pH of theresulting solution was adjusted to ˜7 using a solution of 5M NaOH andthe mixture was then extracted with heptanes (100 mL×3). The combinedorganic fractions were dried (Na₂SO₄), filtered and concentrated underreduced pressure to give 2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde2 (4 g, 49%) as a yellow oil.

Synthesis of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde3: To a degassed solution of2-bromo-4,4-dimethylcyclohex-1-enecarbaldehyde 2 (5 g, 0.023 mol) and4-chlorophenyl boronic acid (3.6 g, 0.023 mol) in 1,4-dioxane (50 mL) atrt was added a solution of 2M Na₂CO₃ (20.4 ml). Nitrogen was bubbledthrough the mixture for 2 min and then PdCl₂(dppf) (0.5 g) was added.The reaction flask was heated to 120° C. where it was maintained for 3h. After this time the suspension was cooled to rt and filtered throughCelite. The collected solids were washed with additional dichloromethaneand the combined filtrate and washings were concentrated under reducedpressure. Purification by column chromatography on silica withPE:EA=20:1 gave2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde 3 (3 g, 53%)as a white solid. MS: 249[M+H]⁺

Synthesis of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4:A solution of 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde3 (20 g, 80.6 mmol) in MeOH (100 mL) was cooled to 0° C., NaBH₄ (3.1 g,80.6 mmol) was added portionwise to the reaction at a rate so that thereaction was maintained at 0-5° C. After added, the mixture was stirredfor 1 h at 0° C. Water was added slowly to the mixture and extractedwith EA (200 mL×3), the organic layer was washed with brine and driedNa₂SO₄, filtered and concentrated under reduced pressure to give(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4 (15 g, 75%)as a white solid. MS: 233[M+H−H₂O]⁺

Synthesisof1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene 5: Asolution of (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol 4(15 g, 0.060 mol) and in Et₂O (300 ml) was cooled to 0° C. beforephosphorus tribromide (7.5 mL) was added dropwise to the mixture, afteradded, the mixture was stirred for 1 h at 0° C. for 90 minutes. Thereaction mixture was added H₂O before being extracted with EA. Theorganic layer was washed with a saturated NaHCO₃ solution and brine anddried Na₂SO₄, filtered and concentrated under reduced pressure to give1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene 5 (18 g,96%) as a colorless oil.

Synthesis of tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate—Toa solution of 1-bromo-2-(bromomethyl)-5,5-dimethylcyclohex-1-ene 5 (21g, 0.067 mol) and tert-butyl piperazine-1-carboxylate (12.4 g, 0.067mol) in dichloromethane (200 ml) at rt was added TEA (12.2 g, 0.12 mol).The reaction was stirred for 2 h. The reaction mixture was concentratedunder reduced pressure to give the crude product. Purification by columnchromatography on silica with PE:EA=20:1 provided tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate6 (21 g, 75%).

Synthesis of1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazinehydrogen chloride: To a solution of tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate6 (30 g, 0.072 mol) in MeOH (20 ml) was added conc. HCl (50 mL). Thereaction was stirred for 24 hours and then concentrated under reducedpressure. A saturated solution of Na₂CO₃ was added to adjust the pH to˜8-9 and the mixture was extracted with dichloromethane (×2). Thecombined extracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The oil product was treated withMeOH/HCl (g) (3M, 500 mL) and stirred for 1 hour, then concentratedunder reduced pressure to get the product1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazinehydrogen chloride IM-14-1 (23 g, 83%). MS: 319[M+H]⁺ ¹H NMR (400 MHz,DMSO) δ 11.51 (s, 1H), 9.60 (s, 1H), 9.18 (s, 1H), 7.45 (d, J=8.2 Hz,2H), 7.15 (d, J=8.0 Hz, 2H), 3.43 (s, 8H), 2.84 (s, 2H), 2.39 (s, 2H),2.03 (s, 2H), 1.45 (t, J=6.0 Hz, 2H), 0.96 (s, 6H).

Example 1-2 Preparation of3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide

To a 500 mL three-neck RB flask equipped with a mechanical stirrer werecharged the 4-chloro-3-nitrobenzenesulfonamide (23.7 g, 100 mmol), DIPEA(12.9 g, 100 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (11.5 g, 100mmol) and acetonitrile (200 mL). The reaction mixture was adjusted to aninternal temperature of 80° C. and agitated for no less than 12 hours.The product solution was cooled down to 40° C. and agitated for no lessthan 1 hour until precipitation observed. The product slurry was furthercooled to 20° C. Water (80 mL) was slowly charged over no less than 1hour, and the mixture cooled to 10° C. and agitated for no less than 2hours before collected by filtration. The wet cake was washed with 1:1mix of acetonitrile:water (40 mL). The wet cake was rinsed with water(80 mL) at 40° C. for no less than 1 hour before collected byfiltration. The wet cake was rinsed with water (20 mL), and dried at 75°C. under vacuum to give the3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide(24.5 g, 78%) as an orange solid. ¹H NMR (400 MHz, DMSO) δ 8.60 (t,J=5.9 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 7.84 (dd, J=9.2, 2.0 Hz, 1H),7.54-7.18 (m, 3H), 3.86 (dd, J=11.3, 3.2 Hz, 2H), 3.35 (s, 2H), 3.27 (t,J=10.9 Hz, 2H), 1.92 (ddd, J=11.2, 7.4, 3.9 Hz, 1H), 1.62 (d, J=11.4 Hz,2H), 1.27 (qd, J=12.3, 4.4 Hz, 2H).

Example 1-3 Preparation of4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide

Into a 50-mL round-bottom flask, was placed(4-fluorooxan-4-yl)methanamine hydrochloride (500 mg, 2.95 mmol, 1.00equiv), 4-fluoro-3-nitrobenzene-1-sulfonamide (650 mg, 2.95 mmol, 1.00equiv), tetrahydrofuran (15 mL), Cs₂CO₃ (2.8 g, 8.59 mmol, 3.00 equiv).The resulting solution was stirred for 14 h at 50° C. in an oil bath.The reaction mixture was cooled to room temperature. The resultingmixture was filtered and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(4:1). This resulted in 650 mg (66%) of4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide as ayellow solid. LCMS (ES, m/z): M+1: 334. H-NMR: (300 MHz, DMSO, ppm): δ8.58 (t, J=6.3 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H), 7.90-7.80 (m, 1H), 7.44(d, J=9.3 Hz, 1H), 7.34 (s, 2H), 3.87-3.70 (m, 4H), 3.61-3.50 (m, 2H),1.95-1.70 (m, 4H).

Example 1-4 Preparation of7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine

Synthesis of5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine:Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of the commerciallyavailable 5-bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (CAS, 1190321-99-3,15 g, 69.76 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL). Thiswas followed by the addition of sodium hydride (4.2 g, 175.00 mmol, 1.50equiv), in portions at 0 degree. After 0.5 h stirring, to this was addedSEM-Cl (14 g, 84.34 mmol, 1.20 equiv) dropwise with stirring at 0degree. The resulting solution was allowed to react, with stirring, foran additional 3 h at room temperature. The reaction was then quenched bythe addition of 300 mL of water. The resulting solution was extractedwith 3×200 mL of ethyl acetate and the organic layers combined. Theresulting mixture was washed with 3×200 mL of brine. The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0:1-1:10). This resulted in 15 g (62%) of5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridineas yellow oil. H-NMR (CDCl₃, 300 MHz) δ: 8.19 (d, J=8.7 Hz, 1H), 7.37(d, J=3.6 Hz, 1H), 6.54 (d, J=3.6 Hz, 1H), 5.64 (s, 2H), 3.58 (t, J=8.1Hz, 2H), 0.98-0.93 (t, J=8.1 Hz, 2H), 0.00 (s, 9H).

Synthesis of5-bromo-6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine:Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 3,3-diethoxypropan-1-ol (2.6 g, 17.38mmol, 1.5 equiv), THF (50 mL). This was followed by the addition of NaH(930 mg, 38.75 mmol, 3.35 equiv), in portions at 0° C. The resultingsolution was stirred for 30 min at 25° C. To this was added a solutionof5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(4 g, 11.58 mmol, 1 equiv) in THF (10 mL) dropwise at 0° C. withstirring. The resulting solution was stirred for 6 hr at 25° C. Thereaction was then quenched by the addition of 500 mL of aqueous NH₄Cl.The resulting solution was extracted with 2×200 mL of ethyl acetate. Theresulting mixture was washed with 1×500 mL of brine. The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:16). This resulted in 4 g (72.92%) of5-bromo-6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridineas yellow oil. ¹H NMR (300 MHz, CDCl₃₋d, ppm) δ 8.03 (s, 1H), 7.15 (d,J=3.6 Hz, 1H), 6.39 (d, J=3.6 Hz, 1H), 5.57 (s, 2H), 4.88 (t, J=5.8 Hz,1H), 4.52 (t, J=6.2 Hz, 2H), 3.75 (dq, J=9.4, 7.1 Hz, 2H), 3.64-3.45 (m,4H), 2.18 (q, J=6.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 6H), 1.01-0.79 (m, 2H),−0.04 (s, 9H). The measurements of the NMR spectra were done with BrukerAvanceIII HD 300 MHz with a probe head of BBOF.

Synthesis of tert-butylN-[6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamate:Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed5-bromo-6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(4 g, 8.45 mmol, 1 equiv), dioxane (50 mL), tert-butyl carbamate (4.9484g, 42.24 mmol, 5.00 equiv), Cs₂CO₃ (13.7627 g, 42.24 mmol, 5.00 equiv),XPhos Pd G3 (1.8 g, 2.11 mmol, 0.25 equiv). The resulting solution wasstirred for 2 hr at 90° C. in an oil bath. The resulting solution wasdiluted with 500 mL of water. The resulting solution was extracted with2×200 mL of ethyl acetate. The resulting mixture was washed with 1×500mL of brine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:16). This resulted in 3.0 g(69.67%) of tert-butylN-[6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamateas light yellow oil. LC-MS: (ES, m/z): M+Na=532, R,T=1.540 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 2.0 minutes; Oventemperature 40° C.; flow: 1.5 mL/min.

Synthesis of4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene: Into a 250-mL round-bottomflask, was placed tert-butylN-[6-(3,3-diethoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]carbamate(3 g, 5.89 mmol, 1 equiv), DCM (120 mL). This was followed by theaddition of TFA (24 mL) dropwise with stirring at 0° C. To this wasadded triethylsilane (6843.7 mg, 58.86 mmol, 10.00 equiv) dropwise withstirring at 0° C. The resulting solution was stirred for 30 min at ° C.,then stirred for 30 min at room temperature. The resulting solution wasdiluted with 500 mL of aqueous NaHCO₃. The resulting solution wasextracted with 2×200 mL of dichloromethane. The resulting mixture waswashed with 1×500 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The crude product waspurified by Flash-Prep-HPLC with the following conditions(IntelFlash-1): Column, C18 reversed phase column; mobile phase, A: H₂O(0.05% NH₃.H₂O+0.05% NH₄HCO₃), B: CH₃CN (15% up to 75% within 15 min);Detector, 220 nm. This resulted in 150 mg (7.98%) of4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene as black oil. ¹H NMR (300MHz, DMSO-d₆, ppm) δ 7.42 (s, 1H), 7.35 (d, J=3.5 Hz, 1H), 6.29 (d,J=3.5 Hz, 1H), 5.43 (s, 2H), 5.17 (d, J=3.9 Hz, 1H), 4.15-3.98 (m, 2H),3.57-3.40 (m, 2H), 3.18-2.96 (m, 2H), 1.91 (d, J=6.7 Hz, 2H), 0.81 (t,J=8.0 Hz, 2H), −0.09 (s, 9H). The measurements of the NMR spectra weredone with Bruker AvanceIII HD 300 MHz with a probe head of BBOF.

Example 1-5 Preparation of13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene

Synthesis of N-(3-hydroxybutyl)-4-methylbenzene-1-sulfonamide. Into a250-mL round-bottom flask purged and maintained with an inert atmosphereof nitrogen, was placed 4-aminobutan-2-ol hydrochloride (4 g, 31.847mmol, 1 equiv), DCM (40 mL), TEA (3.56 g, 35.181 mmol, 1.10 equiv). Thiswas followed by the addition of 4-methylbenzene-1-sulfonyl chloride(6.08 g, 31.893 mmol, 1.00 equiv) in portions at 0 degrees C. Theresulting solution was stirred for 2 h at 25 degrees C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 4.4 g (56.78%) ofN-(3-hydroxybutyl)-4-methylbenzene-1-sulfonamide as colorless oil. ¹HNMR (300 MHz, CDCl₃-d, ppm) δ 7.82-7.73 (d, J=9.0 Hz, 2H), 7.39-7.30 (d,J=9.0 Hz, 2H), 4.06-3.82 (m, 1H), 3.24-3.16 (m, 1H), 3.06-3.00 (m, 1H),2.45 (s, 3H), 1.70-1.55 (m, 2H), 1.20 (d, J=6.2 Hz, 3H).

Synthesis ofN-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]butyl]-4-methylbenzene-1-sulfonamide.Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placedN-(3-hydroxybutyl)-4-methylbenzene-1-sulfonamide (4.4 g, 18.083 mmol,1.10 equiv), THF (60 mL). This was followed by the addition of NaH (1.97g, 49.255 mmol, 3.00 equiv, 60%), in portions at 0 degrees C. Theresulting solution was stirred for 0.5 h at 0 degrees C. To this wasadded5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(5.66 g, 16.392 mmol, 1 equiv). The resulting solution was stirredovernight at 50 degrees C. in an oil bath. The reaction mixture wascooled to 25 degree C. The reaction was then quenched by the addition of500 mL of NH₄Cl. The resulting solution was extracted with 2×200 mL ofethyl acetate and the organic layers combined. The resulting mixture waswashed with 1×500 ml of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 6 g (64.37%) ofN-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]butyl]-4-methylbenzene-1-sulfonamideas colorless oil. ¹H NMR (300 MHz, CDCl₃-d, ppm) δ 8.04 (s, 1H),7.74-7.63 (m, 2H), 7.23-7.11 (m, 3H), 6.41 (d, J=3.6 Hz, 1H), 5.56 (d,J=3.3 Hz, 2H), 5.89-5.33 (m, 1H), 3.59-3.46 (m, 2H), 3.17 (t, J=6.0 Hz,2H), 2.37 (s, 3H), 2.08-1.78 (m, 2H), 1.37 (d, J=6.2 Hz, 3H), 0.94-0.85(m, 2H), −0.06 (s, 9H).

Synthesis of13-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene. Into a 250-mL round-bottomflask purged and maintained with an inert atmosphere of nitrogen, wasplacedN-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]butyl]-4-methylbenzene-1-sulfonamide(6 g, 10.552 mmol, 1 equiv), DMSO (60 mL), pyridine-2-carboxylic acid(1.04 g, 8.448 mmol, 0.80 equiv), CuI (2.41 g, 12.654 mmol, 1.20 equiv),K₂CO₃ (4.38 g, 31.692 mmol, 3.00 equiv). The resulting solution wasstirred for 2 days at 125 degrees C. in an oil bath. The reactionmixture was cooled to 25 degree C. The resulting solution was dilutedwith 500 mL of water. The resulting solution was extracted with 3×200 mLof ethyl acetate and the organic layers combined. The resulting mixturewas washed with 2×1000 ml of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 2.8 g (54.41%) of13-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene as yellow oil. ¹H NMR (300MHz, CDCl₃-d, ppm) δ 8.10 (s, 1H), 7.53-7.40 (m, 2H), 7.30 (d, J=3.6 Hz,1H), 7.24-7.12 (m, 2H), 6.50 (d, J=3.6 Hz, 1H), 5.65 (d, J=10.7 Hz, 1H),5.49 (d, J=10.7 Hz, 1H), 4.37-4.23 (m, 1H), 3.94-3.80 (m, 1H), 3.62-3.36(m, 3H), 2.37 (s, 3H), 1.89-1.64 (m, 2H), 1.23 (d, J=6.3 Hz, 3H),1.01-0.76 (m, 2H), −0.07 (s, 9H).

Synthesis of13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene. Into a 250-mL round-bottomflask purged and maintained with an inert atmosphere of nitrogen, wasplaced Na (793.5 mg, 34.51 mmol, 6.01 equiv), naphthalene (4.42 g, 34.48mmol, 6.01 equiv), DME (20 mL). The mixture was stirred at roomtemperature for 40 min until the formation of Na/naphthalene wascomplete. Another 250-mL round-bottom flask purged and maintained withan inert atmosphere of nitrogen, was placed13-methyl-10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene (2.8 g, 5.741 mmol, 1equiv), THF (20 mL). This was followed by the addition of above solutionat −78 degrees C. The resulting solution was stirred for 3 hr at roomtemperature. The reaction was then quenched by the addition of 500 mL ofNH₄Cl. The resulting solution was extracted with 3×200 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 1×500 ml of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:3). Thisresulted in 1.2 g (62.67%) of13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene as yellow oil. ¹H NMR (300MHz, DMSO-d₆, ppm) δ 7.43-7.26 (m, 2H), 6.27 (d, J=3.5 Hz, 1H), 5.43 (d,J=3.4 Hz, 2H), 5.13 (s, 1H), 4.14-4.04 (m, 1H), 3.58-3.39 (m, 3H),3.28-3.10 (m, 1H), 2.95-2.77 (m, 1H), 2.09-1.85 (m, 1H), 1.85-1.64 (m,1H), 1.37 (d, J=6.3 Hz, 3H), 0.88-078 (m, 2H), −0.09 (s, 9H).

Synthesis of13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene. The crude product (0.5 g)was purified by Chiral-Prep-HPLC with the following conditions:Instrument Name: SHIMADZU LC-20AD, LC parameters: Pump Mode: Binarygradient, Start Conc. of Pump B: 50.0%, Total Flow: 15 mL/min, Phase A:n-Hexane (0.1% DEA), Phase B: Eethanol, Column Name: CHIRALpak IA-3,Length: 50 mm, Internal Diameter: 4.6 mm, Particle Size: 3.0 um, ColumnTemp: 25° C., PDA Model: SPD-M20A, Wavelength: from 190 nm to 500 nm.This resulted in 220 mg (peak 1) [a]=−6.78° (C=0.129 g/100 mL in CH₂Cl₂,T=27° C.) of (13R orS)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene as a yellow oil and 230 mg(peak 2) [a]=+11.84° (C=0.106 g/100 mL in CH₂Cl₂, T=27° C.) of (13S orR)-13-methyl-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene as a yellow oil.

Example 2 Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Synthesis of methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate:Into a 250-mL round-bottom flask, was placed a solution of Example 1-1,i.e,1-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazine(15.09 g, 47.32 mmol, 1.00 equiv) in DMA (150 mL), DIEA (12.9 g, 99.81mmol, 2.00 equiv), methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol,1.00 equiv). The resulting solution was stirred for 12 h at 100 degree.The reaction mixture was cooled to room temperature. The reaction wasthen quenched by the addition of 50 mL of water. The resulting solutionwas extracted with 3×100 mL of ethyl acetate and the organic layerscombined. The resulting mixture was washed with 3×100 mL of brine. Themixture was dried over anhydrous sodium sulfate, then filtered andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:5). This resulted in 7g (crude) of methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoateas yellow oil. LC-MS: (ES, m/z): M+1=533, 531.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate: Into a100-mL round-bottom flask purged and maintained with an inert atmosphereof nitrogen, was placed methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(999.0 mg, 1.88 mmol, 4.00 equiv), toluene (20 mL),4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene (150 mg, 0.47 mmol, 1equiv), Cs₂CO₃ (764.9 mg, 2.35 mmol, 5 equiv), XantPhos Pd 2G (333.2 mg,0.38 mmol, 0.8 equiv). The resulting solution was stirred for 1overnight at 110° C. The resulting solution was diluted with 300 mL ofwater. The resulting solution was extracted with 2×100 mL of ethylacetate. The resulting mixture was washed with 1×300 mL of brine. Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2). This resulted in 200 mg (55.29%) ofmethyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate as a yellowsolid. LC-MS: (ES, m/z): M+H=769, R,T=3.076 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Shim-pack XR-ODS, 2.2 microm; Eluent A: water (0.05% TFA);Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to 100%acetonitrile in 5.0 minutes; Oven temperature 40° C.; flow: 1.5 mL/min.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate: Into a 40-mLvial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate (200 mg, 0.26mmol, 1 equiv), THF (20 mL), TBAF.3H₂O (2.5 g), ethane-1,2-diamine (1.5g, 24.96 mmol, 96.15 equiv). The resulting solution was stirred for 2overnight at 70° C. in an oil bath. The resulting solution was dilutedwith 200 mL of water. The resulting solution was extracted with 3×30 mLof ethyl acetate. The resulting mixture was washed with 2×200 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (2:1). This resulted in 130 mg(78.22%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate as a lightyellow solid. LC-MS: (ES, m/z): M+H=639, R,T=1.388 min. The measurementsof the retention were done with a reversed phase column (C18). ShimadzuLCMS 2020; 50*3.0 Shim-pack XR-ODS, 2.2 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to100% acetonitrile in 2.6 minutes; Oven temperature 40° C.; flow: 1.5mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid: Into a40-mL vial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate (130 mg, 0.20mmol, 1 equiv), MeOH (6 mL), THF (6 mL), H₂O (2 mL), NaOH (81.2 mg, 2.03mmol, 10.00 equiv). The resulting solution was stirred for 1 overnightat 60° C. in an oil bath. The resulting mixture was concentrated undervacuum. The pH value of the solution was adjusted to 5-6 with HCl (2mol/L). The resulting solution was extracted with 2×50 mL ofdichloromethane/MeOH (v:v=10:1). The resulting mixture was washed with2×200 mL of brine. The mixture was dried over anhydrous sodium sulfateand concentrated under vacuum. This resulted in 80 mg (62.92%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid as alight yellow solid. LC-MS: (ES, m/z): M+H=625, R,T=1.336 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Shim-pack XR-ODS, 2.2 microm; EluentA: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient from 5%acetonitrile to 100% acetonitrile in 2.6 minutes; Oven temperature 40°C.; flow: 1.5 mL/min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide: Into a40-mL round-bottom flask, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (50 mg,0.08 mmol, 1 equiv), DCM (3 mL),3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08mmol, 1.00 equiv), EDCI (30.6 mg, 0.16 mmol, 2 equiv), DMAP (39.0 mg,0.32 mmol, 4 equiv). The resulting solution was stirred for overnight at25 degrees C. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (10:1). The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18 reversed phase column; mobile phase, Water (10 MMOL/L NH₄HCO₃+0.05%NH₃.H₂O) and CH₃CN (20.0% CH₃CN up to 90.0% in 30 min); Detector, UV 220nm. This resulted in 19.1 mg (25.90%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellowsolid. LC-MS: (ES, m/z): M+1=923, R,T=3.463 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Agilent Poroshell HPH-C18, 2.7 um; Eluent A: water (0.05%ammonia water); Eluent B: Acetonitrile; linear gradient from 5%acetonitrile to 95% acetonitrile in 7.0 minutes; Oven temperature 40°C.; flow: 1.5 mL/min. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 11.91 (s, 1H),11.26 (s, 1H), 8.56 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 7.61 (d, J=9.0 Hz,1H), 7.48 (d, J=9.2 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.20 (s, 1H), 7.07(d, J=8.3 Hz, 2H), 6.99-6.83 (m, 2H), 6.76 (d, J=29.2 Hz, 2H), 6.14 (s,1H), 4.21 (s, 2H), 3.85 (d, J=9.3 Hz, 2H), 3.52 (s, 2H), 3.30-3.14 (m,8H), 2.79 (s, 1H), 2.23 (d, J=20.0 Hz, 5H), 1.99 (s, 4H), 1.85 (s, 1H),1.61 (d, J=11.3 Hz, 2H), 1.42 (s, 2H), 1.25 (s, 2H), 1.03-0.79 (m, 6H).The measurements of the NMR spectra were done with Bruker AvanceIII HD300 MHz with a probe head of BBOF.

Example 3 Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

Into a 40-mL vial, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (80 mg,0.13 mmol, 1 equiv), DCM (3 mL),4-[[(4-fluorooxan-4-yl)methyl]amino]-3-nitrobenzene-1-sulfonamide (42.6mg, 0.13 mmol, 1.00 equiv), EDCI (49.0 mg, 0.26 mmol, 2 equiv), DMAP(62.4 mg, 0.51 mmol, 4 equiv). The resulting solution was stirred for 1overnight at 25° C. The resulting mixture was concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-006): Column, X Bridge Prep C18 OBD Column, 19×150mm 5 um; mobile phase, Water (10 MMOL/L NH₄HCO₃+0.1% NH₃.H₂O) and CH₃CN(41.0% CH₃CN up to 61.0% in 6 min, hold 95.0% in 1 min, down to 41.0% in1 min, hold 41.0% in 1 min); Detector, UV 210 nm. This resulted in 17 mg(14.13%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamideas a yellow solid. LC-MS: (ES, m/z): M+1=940, R,T=1.583 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradientfrom 5% acetonitrile to 100% acetonitrile in 3.0 minutes; Oventemperature 40° C.; flow: 1.5 mL/min. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ11.94 (s, 1H), 11.25 (s, 1H), 8.59 (s, 1H), 8.48 (d, J=2.3 Hz, 1H), 7.66(d, J=9.1 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.20(d, J=3.1 Hz, 1H), 7.07 (dd, J=8.9, 3.8 Hz, 3H), 6.94 (s, 1H), 6.71 (s,2H), 6.13 (d, J=3.1 Hz, 1H), 4.20 (d, J=6.5 Hz, 2H), 3.80-3.70 (m, 3H),3.68-3.60 (m, 1H), 3.58-3.45 (m, 4H), 3.25-3.05 (m, 4H), 2.83-2.69 (m,2H), 2.33-2.10 (m, 6H), 1.98 (s, 4H), 1.84-1.68 (m, 4H), 1.49-1.35 (m,2H), 0.95 (s, 6H). The measurements of the NMR spectra were done withBruker AvanceIII HD 300 MHz with a probe head of BBOF.

Example 4 Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide

Synthesis of 4,4,4-trifluoro-3-hydroxybutanamide: Into a 50-mLround-bottom flask, was placed ethyl 4,4,4-trifluoro-3-hydroxybutanoate(500 mg, 2.7 mmol, 1 equiv), NH₃ in MeOH (5 mL, 4.0 M). The resultingsolution was stirred for 16 hr at 60 degrees C. The resulting mixturewas concentrated. This resulted in 500 mg of4,4,4-trifluoro-3-hydroxybutanamide as a white solid. ¹H NMR (300 MHz,DMSO-d₆, ppm) δ 7.62 (ds, 1H), 7.01 (ds, 1H), 3.36-6.34 (m, 1H),4.27-4.40 (m, 1H), 2.39-2.36 (m, 2H). The measurements of the NMRspectra were done with Bruker AvanceIII HD 300 MHz with a probe head ofBBOF.

Synthesis of 4-amino-1,1,1-trifluorobutan-2-ol: Into a 50-mL 3-neckedround-bottom flask, was placed 4,4,4-trifluoro-3-hydroxybutanamide (500mg, 3.2 mmol, 1 equiv) and THF (10 mL), LAH (242 mg, 6.4 mmol, 2.00equiv) was added little by little at ice-bath. The resulting solutionwas stirred for 16 hr at R,T. After the reaction was completed, thereaction mixture was quenched by the addition of 0.24 mL of water, 0.24mL of NaOH (10% in H₂O) and 0.72 mL of water was added into the solutionsuccessively at ice-bath. The solids were filtered out. The resultingmixture was concentrated under vacuum. This resulted in 380 mg (83.43%)of 4-amino-1,1,1-trifluorobutan-2-ol as a colorless oil. ¹H NMR (300MHz, CDCL3, ppm) 4.10-4.01 (m, 1H), 2.70-2.66 (m, 2H), 1.51-1.47 (m,2H). The measurements of the NMR spectra were done with Bruker AvanceIIIHD 300 MHz with a probe head of BBOF.

Synthesis of4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzenesulfonamide. Into a100-mL round-bottom flask, was placed 4-amino-1,1,1-trifluorobutan-2-ol(350 mg, 2.4 mmol, 1 equiv), TEA (480 mg, 4.8 mmol, 2.0 equiv) and DCM(10 mL), TsCl (470 mg, 2.4 mmol, 1.0 equiv) was added at ice-bath. Theresulting solution was stirred for 4 hr at R,T degrees C. The resultingsolution was diluted with 50 mL of DCM. The resulting mixture was washedwith 2×20 ml of water and 1×20 mL of brine. The mixture was dried overanhydrous sodium sulfate. The solids were filtered out. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (0-50%). Thisresulted in 600 mg (82.52%) of4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzene-1-sulfonamide ascolorless oil. ¹H NMR (300 MHz, DMSO-d₆, ppm) δ 7.70-7.68 (m, 2H),7.42-7.40 (m, 2H), 6.23-6.21 (m, 1H), 4.01-3.96 (m, 1H), 2.87-2.83 (m,2H), 2.39 (s, 3H), 1.70-1.49 (m, 2H). The measurements of the NMRspectra were done with Bruker AvanceIII HD 300 MHz with a probe head ofBBOF.

Synthesis ofN-(3-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)-4,4,4-trifluorobutyl)-4-methylbenzenesulfonamide.Into a 100-mL round-bottom flask, was placed5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(300 mg, 0.9 mmol, 1 equiv),4-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)benzene-1-sulfonamide (310mg, 1.0 mmol, 1.2 equiv), Cs₂CO₃ (566 mg, 1.7 mmol, 2.0 equiv) and1,4-Dioxane (10 mL). The resulting solution was stirred for 16 hr at 90degrees C. in an oil bath. The reaction mixture was cooled. The solidswere filtered out. The resulting solution was diluted with 100 mL ofDCM. The resulting mixture was washed with 5×50 ml of water and 1×50 mLof brine. The mixture was dried over anhydrous sodium sulfate. Thesolids were filtered out. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (0-30%). This resulted in 400 mg (73.95%) ofN-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1-sulfonamideas a light yellow solid. ¹H NMR (300 MHz, CDCL3, ppm) 8.17 (bs, 1H),7.76-7.73 (m, 2H), 7.29-7.27 (m, 3H), 6.51-6.50 (m, 1H), 5.93-5.91 (m,1H), 5.75-5.72 (m, 2H), 5.63-5.58 (m, 1H), 3.60-3.57 (m, 2H), 3.34-3.32(m, 1H), 3.13-3.11 (m, 1H), 2.46 (s, 3H), 2.31-2.29 (m, 1H), 2.10-2.07(m, 1H), 1.00-0.85 (m, 2H), 0.01 (s, 9H). The measurements of the NMRspectra were done with Bruker AvanceIII HD 300 MHz with a probe head ofBBOF.

Synthesis of1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane.Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placedN-[3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-4,4,4-trifluorobutyl]-4-methylbenzene-1-sulfonamide(700 mg, 1.13 mmol, 1 equiv), Cs₂CO₃ (1.1 g, 3.39 mmol, 3.00 equiv), CuI(214 mg, 1.13 mmol, 1.0 equiv), 2-isobutyrylcyclohexan-1-one (80 mg,0.56 mmol, 0.5 equiv), DMSO (10 mL), The resulting solution was stirredfor 24 hr at 120° C. in an oil bath. The resulting solution was dilutedwith 20 mL of water. The resulting solution was extracted with 2×50 mLof ethyl acetate. The resulting mixture was washed with 1×50 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0-30%). This resulted in 350mg (57.38%) of1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepineas light yellow solid. ¹H NMR (300 MHz, CDCL3, ppm) 8.19 (bs, 1H),7.50-7.47 (m, 2H), 7.39 (s, 1H), 7.24-7.22 (m, 2H), 6.58-6.57 (m, 1H),5.69-5.66 (m, 1H), 5.55-5.51 (m, 1H), 4.57-4.52 (m, 1H), 3.96-3.94 (m,1H), 3.59-3.56 (m, 2H), 3.48-3.44 (m, 1H), 2.41 (s, 3H), 2.31-2.29 (m,1H), 1.95-1.91 (m, 1H), 0.97-0.91 (m, 2H), 0.05 (s, 9H). Themeasurements of the NMR spectra were done with Bruker AvanceIII HD 300MHz with a probe head of BBOF.

Synthesis of4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane.Into a 250 mL 3-necked round-bottom flask, was placed Na (150 mg, 6.5mmol, 1.0 equiv), naphthalene (833 mg, 6.5 mmol, 10 equiv) and DME (3ml) under N₂. The reaction mixture was stirred at room temperature untilNa and naphthalene completely dissolved. To this was added the solution1-tosyl-4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine(350 mg, 0.65 mmol, 1 equiv) in THF (5 mL) at −78° C. The resultingsolution was stirred for 2-3 hr at −60° C. to −40° C. unstill thestarting material consumed by TLC. The reaction was then quenched by theaddition of 5 mL of NH₄Cl at −10° C. The resulting solution wasextracted with 3×10 mL of ethyl acetate. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1/3). This resulted in 220 mg (88%) of4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepineas a white solid.

Synthesis of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate.Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(1.2 g, 2.28 mmol, 4.00 equiv), toluene (20 mL),4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine(220 mg, 0.57 mmol, 1 equiv), Cs₂CO₃ (923 mg, 2.84 mmol, 5 equiv),XantPhos Pd 2G (250 mg, 0.46 mmol, 0.8 equiv). The resulting solutionwas stirred for overnight at 110° C. The resulting solution was dilutedwith 30 mL of water. The resulting solution was extracted with 2×30 mLof ethyl acetate. The resulting mixture was washed with 1×30 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0-50%). This resulted in 380mg crude (80.0%) of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoateas a yellow solid. LC-MS: (ES, m/z): M+H=838, R,T=3.33 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0, Poroshell HPH-C18, 2.7 microm; EluentA: water (0.05% NH4HCO3); Eluent B: Acetonitrile; linear gradient from5% acetonitrile to 100% acetonitrile in 5.0 minutes; Oven temperature40° C.; flow: 1.5 mL/min.

Synthesis of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate.Into a 40-mL vial, was placed methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate(380 mg, 0.45 mmol, 1 equiv), THF (20 mL), TBAF.3H₂O (708 mg, 2.25 mmol,5 equiv), ethane-1,2-diamine (540 mg, 9.0 mmol, 20 equiv). The resultingsolution was stirred for overnight at 70° C. in an oil bath. Theresulting solution was diluted with 20 mL of water. The resultingsolution was extracted with 3×30 mL of ethyl acetate. The resultingmixture was washed with 2×20 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(0-50%). This resulted in 300 mg (93%) of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoateas a light yellow solid. ¹H NMR (300 MHz, CDCL3, ppm) 10.78 (bs, 1H),7.75-7.72 (m, 1H), 7.29-7.24 (m, 3H), 7.00-6.97 (m, 2H), 6.59-6.56 (m,2H), 6.28-6.26 (m, 1H), 5.28-5.20 (m, 1H), 3.98-3.96 (m, 1H), 3.79-3.77(m, 1H), 3.59 (s, 1H), 3.24-3.23 (m, 3H), 2.84 (m, 2H), 2.31-2.28 (m,4H), 2.26-2.24 (m, 4H), 1.49-1.47 (m, 2H), 1.34-1.24 (m, 4H), 1.00 (s,6H), 0.96-0.90 (m, 2H).

Synthesis of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoicacid. Into a 40-mL vial, was placed methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate(200 mg, 0.28 mmol, 1 equiv), MeOH (6 mL), 1,4-dioxane (6 mL), H₂O (2mL), NaOH (67 mg, 1.68 mmol, 6.00 equiv). The resulting solution wasstirred for overnight at 60° C. in an oil bath. The resulting mixturewas concentrated under vacuum. The pH value of the solution was adjustedto 5-6 with HCl (2 mol/L). The resulting solution was extracted with2×50 mL of dichloromethane/MeOH (v:v=10:1). The resulting mixture waswashed with 2×200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 157 mg(81.0%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoicacid as a light yellow solid. LC-MS: (ES, m/z): M+H=694, R,T=2.43 min.The measurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0, Poroshell HPH-C18, 2.7 microm; EluentA: water (0.05% NH4HCO3); Eluent B: Acetonitrile; linear gradient from5% acetonitrile to 100% acetonitrile in 5.0 minutes; Oven temperature40° C.; flow: 1.5 mL/min.

Synthesis of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide.Into a 40-mL round-bottom flask, was placed4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoicacid (57 mg, 0.08 mmol, 1 equiv), DCM (3 mL),3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08mmol, 1.00 equiv), EDCI (30.6 mg, 0.16 mmol, 2 equiv), DMAP (39.0 mg,0.32 mmol, 4 equiv). The resulting solution was stirred for overnight at25 degrees C. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (10:1). The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18 reversed phase column; mobile phase, Water (10 MMOL/L NH₄HCO₃+0.05%NH₃.H₂O) and CH₃CN (20.0% CH₃CN up to 90.0% in 30 min); Detector, UV 220nm. This resulted in 32 mg (40.0%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-2-(4-(trifluoromethyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamideas a yellow solid. LC-MS: (ES, m/z): M+1=991, R,T=2.41 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Agilent Poroshell HPH-C18, 2.7 um;Eluent A: water (0.05% ammonia water); Eluent B: Acetonitrile; lineargradient from 5% acetonitrile to 95% acetonitrile in 7.0 minutes; Oventemperature 40° C.; flow: 1.5 mL/min. ¹H NMR (300 MHz, CDCL3, ppm) δ11.43 (ds, 1H), 9.99 (ds, 1H), 8.72 (s, 1H), 8.40 (ds, 1H), 7.93-7.85(m, 2H), 7.37-7.35 (m, 2H), 7.26 (s, 1H), 7.02-6.93 (m, 3H), 6.71-6.64(m, 3H), 6.27 (s, 1H), 4.58 (s, 1H), 4.05-3.15 (m, 23H), 2.70-2.35 (m,7H), 2.03 (s, 3H), 1.92-1.90 (m, 1H), 1.89-1.87 (m, 2H), 1.71-1.67 (m,2H), 1.53-1.45 (m, 3H), 1.00 (s, 6H). The measurements of the NMRspectra were done with Bruker AvanceIII HD 300 MHz with a probe head ofBBOF.

Example 5 Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]thiazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Synthesis of methyl3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propanoate.Into a 40-mL round-bottom flask, was placed5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(3 g, 8.7 mmol, 1 equiv), methyl 3-sulfanylpropanoate (2.1 g, 17.4 mmol,2.0 equiv), ACN (30 mL), Cs₂CO₃ (7.1 g, 21.7 mmol, 2.5 equiv). Theresulting solution was stirred for 1 hr at 70° C. The solids werefiltered out. The resulting mixture was concentrated. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(0-10%). This resulted in 300 mg (7.75%) of methyl3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propanoateas a colorless oil. LC-MS: (ES, m/z): M+1=445/447, R,T=1.47 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient.

Synthesis of3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propan-1-ol.Into a 8-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propanoate(300 mg, 0.67 mmol, 1 equiv) and THF (10 mL). This was followed by theaddition of LiAlH₄ (51 mg, 1.3 mmol, 2.00 equiv) at −78° C. carefully.The resulting solution was stirred for 1 hr at room temperature. Afterthe reaction was completed, the reaction mixture was quenched by theaddition of 0.5 mL of water, 0.5 mL of NaOH (10% in H₂O) and 1.5 mL ofwater was added into the solution successively at ice-bath. The solidswere filtered out. The resulting mixture was concentrated under vacuum.This resulted in 200 mg (71.14%) of3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propan-1-olas yellow oil. H-NMR: (CDCl3, 300 ppm): 7.99 (s, 1H), 7.24-7.20 (m, 1H),6.49-6.41 (m, 1H), 5.32 (s, 2H), 3.84-3.78 (m, 2H), 3.58-3.50 (m, 2H),3.46-3.40 (m, 2H), 2.09-2.01 (m, 2H), 0.96-0.88 (m, 2H), 0.05 (s, 9H).

Synthesis ofN-[6-[(3-hydroxypropyl)sulfanyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide.Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed 4-methylbenzene-1-sulfonamide (1.6 g,9.6 mmol, 2 equiv),3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)sulfanyl]propan-1-ol(2 g, 4.8 mmol, 1 equiv), 1,10-phenanthroline (0.17 g, 0.94 mmol, 0.20equiv), CuI (0.18 g, 0.96 mmol, 0.2 equiv), Cs₂CO₃ (3.1 g, 9.6 mmol, 2equiv) under DMSO (30 mL). The resulting solution was stirred for 72 hrat 120° C. The resulting solution was diluted with 30 mL of H₂O. Thesolids were filtered out. The resulting solution was extracted with 3×50mL of ethyl acetate, The mixture was dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0:1-1:1). This resulted in1.0 g (41.11%) ofN-[6-[(3-hydroxypropyl)sulfanyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamideas a white solid. LC-MS: (ES, m/z): M+1=508, R,T=2.845 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient.

Synthesis of10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene. Into a 8-mL round-bottomflask, was placedN-[6-[(3-hydroxypropyl)sulfanyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide(240 mg, 0.47 mmol, 1 equiv), THF (5 ml), PPh₃ (248 mg, 0.95 mmol, 2equiv). This was followed by the addition of DEAD (164 mg, 0.95 mmol,2.00 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 12 hrs at room temperature. The resulting mixture wasconcentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (0:1-1:2). This resulted in 200 mg(86.40%) of10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene as a colorless solid.H-NMR: (CDCl3, 300 ppm): 7.82 (s, 1H), 7.69-7.58 (m, 3H), 7.38-7.36 (d,J=6Hz, 2H), 6.55-6.54 (d, J=3Hz, 2H), 5.55 (s, 2H), 4.30-4.23 (m,2H)4.06-4.02 (m, 2H), 3.57-3.49 (m, 2H), 2.77 (s, 2H), 2.50 (s, 3H),2.07-1.99 (m, 3H), 1.24-1.04 (m, 9H), 0.87-0.84 (m, 3H), 0.02 (s, 9H).

Synthesis of4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene. Into a 8-mL round-bottomflask, was placed naphthalene (314 mg, 2.4 mmol, 6 equiv), Na (90 mg,3.9 mmol, 9.6 equiv) and DME (5 mL), The resulting solution was stirredfor 0.5 hr at room temperature. The resulting solution was added to40-mL round-bottom flask of10-(4-methylbenzenesulfonyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene (200 mg, 0.41 mmol, 1equiv), THF (10 mL). The resulting solution was stirred for 3 hr at roomtemperature. The reaction was then quenched by the addition of 1 mL ofNH₄Cl. The resulting mixture was concentrated. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (0-50%).This resulted in 120 mg (87.57%) of4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene as a yellow solid.LC-MS:(ES, m/z): M+1=649, R,T=0.80 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate. Into a 8-mLround-bottom flask purged and maintained with an inert atmosphere ofnitrogen, was placed4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene (120 mg, 0.36 mmol, 1equiv), methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(380 mg, 0.71 mmol, 2.00 equiv), caesio methaneperoxoate caesium (233mg, 0.71 mmol, 2.00 equiv), toluene (3 mL), XantPhosPd (34 mg, 0.04mmol, 0.1 equiv). The resulting solution was stirred for overnight at110° C. The resulting mixture was concentrated. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (0-50%).This resulted in 150 mg (53.32%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate as a yellowsolid. LC-MS: (ES, m/z): M+1=786, R,T=1.26 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient. H-NMR: (CDCl3, 300 ppm):7.64-7.61 (d, J=9 Hz, 1H), 7.35 (s, 1H), 7.28-7.26 (m, 2H), 7.19-7.18(m, 1H), 6.99-6.97 (m, 2H), 6.52-6.47 (m, 2H), 6.27-6.26 (d, J=3Hz, 1H),5.61 (s, 2H), 3.96-3.84 (m, 2H), 3.60-3.54 (m, 5H), 3.28-3.16 (m, 6H),2.82 (s, 2H), 2.33-2.24 (m, 6H), 2.06-2.02 (m, 4H), 1.49-1.45 (m, 2H),1.28-1.19 (m, 4H), 1.03-0.88 (m, 6H), 0.00 (s, 9H).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate. Into a 8-mLround-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate (150 mg, 0.19mmol, 1 equiv), ethane-1,2-diamine (229 mg, 3.8 mmol, 20 equiv), TBAF(997 mg, 3.8 mmol, 20 equiv), THF (10 mL). The resulting solution wasstirred for 14 hr at 70° C. The resulting mixture was concentrated. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0-50%). This resulted in 50 mg (39.95%) ofmethyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate as a yellowsolid. LC-MS: (ES, m/z): M+1=656, R,T=1.05 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Into a8-mL round-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate (65 mg, 0.10mmol, 1 equiv), 1,4-dioxane (1 mL), H₂O (1 mL), NaOH (23.95 mg, 0.60mmol, 6.00 equiv). The resulting solution was stirred for 14 hr at 90°C. The pH value of the solution was adjusted to 5 with HCl (2 mol/L).The resulting mixture was concentrated. The residue was applied onto asilica gel column with dichloromethane/methanol (0-10%). This resultedin 30 mg (46.80%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid as ayellow solid.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide. Into a 8-mLround-bottom flask, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (30 mg,0.05 mmol, 1 equiv),3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (17 mg, 0.06mmol, 1.20 equiv), EDCI (18 mg, 0.09 mmol, 2 equiv), DMAP (23 mg, 0.19mmol, 4 equiv), DCM (3 mL). The resulting solution was stirred forovernight at room temperature. The resulting mixture was concentrated.The crude product was purified by Flash-Prep-HPLC with the followingconditions (IntelFlash-1): Column, C18 silica gel; mobile phase, Water(0.1% FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in 1 min,down to 48.0% in 1 min within 5; Detector, UV 254 nm. This resulted in10.6 mg (24.15%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellowsolid. LC-MS: (ES, m/z): M+1=939, R,T=3.55 min. The measurements of theretention were done with a reversed phase column (C18). Shimadzu LCMS2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm; Eluent A: water (0.05%TFA); Eluent B: Acetonitrile; linear gradient. H-NMR: (CDCl3, 300 ppm):8.71 (s, 1H), 8.49 (s, 1H), 7.99-7.97 (m, 1H), 7.81-7.77 (m, 1H),7.38-7.28 (m, 4H), 7.01-6.93 (m, 2H), 6.88-6.72 (m, 3H), 3.36 (s, 1H),4.06-3.26 (m, 18H), 2.73-2.22 (m, 6H), 2.13-1.73 (m, 3H), 1.79-1.25 (m,6H), 1.00 (s, 6H).

Example 6 Preparation of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate: Into a 8-mLround-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate (30 mg, 0.046mmol, 1 equiv), DCM (3 mL), m-CPBA (19.72 mg, 0.114 mmol, 2.50 equiv).The resulting solution was stirred for overnight at room temperature.The reaction was then quenched by the addition of 1 mL of water. Theresulting solution was extracted with 2×5 mL of dichloromethaneconcentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (0:1-1:1). This resulted in 20 mg (63.57%)of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate as a whitesolid. LC-MS-PH-PHNW-4-65-8: (ES, m/z): M+1=688, R,T=0.967 min. Themeasurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Into a8-mL round-bottom flask, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate(20 mg, 0.029mmol, 1 equiv), 1,4-dioxane (1 mL), water (1 mL), NaOH (6.97 mg, 0.174mmol, 6.00 equiv). The resulting solution was stirred for overnight at70° C. The pH value of the solution was adjusted to 5 with HCl (1mol/L). The resulting solution was extracted with 2×3 mL of ethylacetate. The organic layer was washed with 2×3 ml of Brine. The mixturewas dried over anhydrous sodium sulfate and concentrated. This resultedin 13 mg (66.35%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid as awhite solid. LC-MS-PH-PHNW-4-65-9: (ES, m/z): M+1=674, R,T=1.945 min.The measurements of the retention were done with a reversed phase column(C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6 microm;Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; linear gradient.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamide.Into a 8-mL round-bottom flask, was placed3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (6.08 mg,0.019 mmol, 1 equiv),4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (13 mg,0.019 mmol, 1 equiv), DCM (0.47 mL, 5.506 mmol, 381.56 equiv), DMAP(9.42 mg, 0.077 mmol, 4 equiv), EDCI (7.39 mg, 0.039 mmol, 2 equiv). Theresulting solution was stirred for overnight at room temperature. Theresulting mixture was concentrated. The crude product was furtherpurified by Prep-HPLC with the following conditions (Waters I): Column,Xbridge Prep C18 OBD column, Sum, 19*150 mm; mobile phase, Water (0.05%TFA) and CH3CN (46% CH3CN up to 51% in 7 min); Detector, UV 220&254 nm.This resulted in 2.5 mg (6.24%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14,14-dioxo-14lambda6-thia-2,4,10-triazatricyclo[7.5.0.0{circumflexover( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]-N-(3-nitro-4-[[(oxan-4-yl)methyl]amino]benzenesulfonyl)benzamideas a yellow solid. LC-MS-PH-PHNW-4-65-0: (ES, m/z): M+1=971.5, R,T=3.243min. The measurements of the retention were done with a reversed phasecolumn (C18). Shimadzu LCMS 2020; 50*3.0 Kinetex 2.6u XB-C18, 2.6microm; Eluent A: water (0.05% TFA); Eluent B: Acetonitrile; lineargradient

Example 7 Preparation of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Synthesis of 2-methoxypropane-1,3-diol. Into a 1000-mL 3-neckedround-bottom flask purged and maintained with an inert atmosphere ofnitrogen, was placed 1,3-dimethyl 2-methoxypropanedioate (20 g, 123mmol, 1 equiv) and THF (250 mL). LiAlH4 (23.4 g, 616 mmol, 5.0 equiv)was added little by little at ice-bath. The resulting solution wasstirred for 16 hr at R,T. After the reaction was completed, the reactionmixture was quenched by the addition of 23.4 mL of water, 23.4 mL ofNaOH (10% in H₂O) and 70 mL of water was added into the solutionsuccessively at ice-bath. The solids were filtered out. The resultingmixture was concentrated under vacuum. This resulted in 12 g (91.67%) of2-methoxypropane-1,3-diol as colorless oil. ¹H NMR (300 MHz, CDCL3, ppm)δ 3.80-3.63 (m, 4H), 3.47 (s, 3H), 3.36-3.32 (m, 1H), 3.25 (bs, 2H).

Synthesis of3-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yloxy)-2-methoxypropan-1-ol.I Into a 250-mL 3-necked round-bottom flask, was placed2-methoxypropane-1,3-diol (1.84 g, 17.4 mmol, 1.2 equiv) and THF (70mL), NaH (0.87 g, 36.2 mmol, 2.5 equiv) was added at ice-bath, after themixture was stirred at R,T for 30 min, and then5-bromo-6-fluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridine(5.0 g, 14.5 mmol, 1 equiv) was added at R,T. The resulting solution wasstirred for 4 hr at 80 degrees C. The reaction was then quenched by theaddition of 20 mL of water. The resulting solution was extracted with3×50 mL of dichloromethane and the organic layers combined. Theresulting mixture was washed with 1×50 mL of brine. The mixture wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (0-40%). Thisresulted in 4.0 g (64.03%) of3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-2-methoxypropan-1-olas a white solid. ¹H NMR (300 MHz, CDCL3, ppm) 8.09 (s, 1H), 7.20 (d,J=3.6 Hz, 1H), 6.44 (d, J=3.6 Hz, 1H), 5.62 (s, 2H), 4.60-4.58 (m, 2H),3.97-3.95 (m, 1H), 3.92-3.90 (m, 2H), 3.79 (s, 3H), 3.65-3.60 (m, 2H),0.98-0.93 (m, 2H), 0.01 (s, 9H).

Synthesis ofN-(6-(3-hydroxy-2-methoxypropoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-methylbenzenesulfonamide.Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed3-[(5-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy]-2-methoxypropan-1-ol(4.0 g, 9.3 mmol, 1 equiv), T_(s)-NH₂ (4.76 g, 27.8 mmol, 3.00 equiv),Cs₂CO₃ (9.06 g, 27.8 mmol, 3.0 equiv), CuI (0.88 g, 4.6 mmol, 0.5equiv), 1,10-phenanthroline (0.50 g, 2.8 mmol, 0.3 equiv) and DMSO (100mL). The resulting solution was stirred for 24 hr at 120 degrees C. inan oil bath. The reaction mixture was cooled. The resulting solution wasdiluted with 500 mL of DCM. The solids were filtered out. The mixturewas dried over anhydrous sodium sulfate. The solids were filtered out.The resulting mixture was concentrated. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (0-60%). Thisresulted in 2.7 g (55.82%) ofN-[6-(3-hydroxy-2-methoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamideas a solid. ¹H NMR (300 MHz, CDCL3, ppm) 8.09 (s, 1H), 7.61-7.59 (m,2H), 7.17-7.15 (m, 3H), 6.75 (s, 1H), 6.46 (d, J=3.3 Hz, 1H), 5.48 (s,2H), 4.28-4.23 (m, 2H), 3.59-3.44 (m, 8H), 2.37 (s, 3H), 0.92-0.86 (m,3H), 0.01 (s, 9H).

Synthesis of3-methoxy-1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane.Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placedN-[6-(3-hydroxy-2-methoxypropoxy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-4-methylbenzene-1-sulfonamide(500 mg, 0.96 mmol, 1 equiv), PPh₃ (1.2 g, 4.79 mmol, 5.0 equiv) and THF(10 mL), DEAD (834 mg, 4.79 mmol, 5.0 equiv) was added dropwise atice-bath. The resulting solution was stirred for 2 hr at R,T. Theresulting solution was diluted with 50 mL of DCM. The resulting mixturewas washed with 3×20 ml of water and 1×20 mL of brine. The mixture wasdried over anhydrous sodium sulfate. The solids were filtered out. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (0-60%).This resulted in 370 mg (76.65%) of3-methoxy-1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepineas a white solid. LC-MS: (ES, m/z): M+H=504, R,T=2.40 min.

Synthesis of3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepane.Into a 250 mL 3-necked round-bottom flask, was placed Na (158 mg, 6.9mmol, 1.0 equiv), naphthalene (884 mg, 6.9 mmol, 10 equiv) and DME (3ml) under N₂. The reaction mixture was stirred at room temperature untilNa and naphthalene completely dissolved. To this was added the solution3-methoxy-1-tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine(350 mg, 0.69 mmol, 1 equiv) in THF (5 mL) at −78° C. The resultingsolution was stirred for 2-3 hr at −60° C. to −40° C. unstill thestarting material consumed by TLC. The reaction was then quenched by theaddition of 5 mL of NH₄Cl at −10° C. The resulting solution wasextracted with 3×10 mL of ethyl acetate. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1/3). This resulted in 214 mg (88%) of3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepineas a white solid. LC-MS: (ES, m/z): M+H=350, R,T=2.26 min.

Synthesis of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate.Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(1.34 g, 2.52 mmol, 4.00 equiv), toluene (20 mL),3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine(220 mg, 0.63 mmol, 1 equiv), Cs₂CO₃ (1.02 g, 3.15 mmol, 5 equiv),XantPhos Pd 2G (25 mg, 0.06 mmol, 0.1 equiv). The resulting solution wasstirred for overnight at 110° C. The resulting solution was diluted with30 mL of water. The resulting solution was extracted with 2×30 mL ofethyl acetate. The resulting mixture was washed with 1×30 mL of brine.The mixture was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (0-50%). This resulted in 403 mg crude(80.0%) of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoateas a yellow solid.

Synthesis of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate.Into a 40-mL vial, was placed methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate(380 mg, 0.48 mmol, 1 equiv), THF (20 mL), TBAF.3H₂O (756 mg, 2.4 mmol,5 equiv), ethane-1,2-diamine (576 mg, 9.6 mmol, 20 equiv). The resultingsolution was stirred for overnight at 70° C. in an oil bath. Theresulting solution was diluted with 20 mL of water. The resultingsolution was extracted with 3×30 mL of ethyl acetate. The resultingmixture was washed with 2×20 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(0-50%). This resulted in 338 mg (93%) of methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoateas a light yellow solid. LC-MS: (ES, m/z): M+H=670, R,T=2.00 min.

Synthesis of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoicacid. Into a 40-mL vial, was placed methyl4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoate(200 mg, 0.30 mmol, 1 equiv), MeOH (6 mL), 1,4-dioxane (6 mL), H₂O (2mL), NaOH (72 mg, 1.8 mmol, 6.00 equiv). The resulting solution wasstirred for overnight at 60° C. in an oil bath. The resulting mixturewas concentrated under vacuum. The pH value of the solution was adjustedto 5-6 with HCl (2 mol/L). The resulting solution was extracted with2×50 mL of dichloromethane/MeOH (v:v=10:1). The resulting mixture waswashed with 2×200 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in 152 mg(81.0%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoicacid as a light yellow solid. LC-MS: (ES, m/z): M+H=656, R,T=2.43 min.

Synthesis of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.Into a 40-mL round-bottom flask, was placed4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzoicacid (50 mg, 0.08 mmol, 1 equiv), DCM (3 mL),3-nitro-4-[[(oxan-4-yl)methyl]amino]benzene-1-sulfonamide (25.2 mg, 0.08mmol, 1.00 equiv), EDCI (30.6 mg, 0.16 mmol, 2 equiv), DMAP (39.0 mg,0.32 mmol, 4 equiv). The resulting solution was stirred for overnight at25 degrees C. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (10:1). The crude product was purified byFlash-Prep-HPLC with the following conditions (IntelFlash-1): Column,C18 reversed phase column; mobile phase, Water (10 MMOL/L NH₄HCO₃+0.05%NH₃.H₂O) and CH₃CN (20.0% CH₃CN up to 90.0% in 30 min); Detector, UV 220nm. This resulted in 32 mg (40.0%) of4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3-methoxy-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamideas a yellow solid. LC-MS: (ES, m/z): M+1=953, R,T=3.44 min. ¹H NMR (300MHz, DMSO-d6, ppm) δ 11.00 (ds, 1H), 8.56 (s, 2H), 7.47-7.44 (m, 2H),7.36-7.33 (m, 2H), 7.08-7.04 (m, 3H), 6.78-6.65 (m, 2H), 6.57-6.54 (m,1H), 6.43 (s, 1H), 6.04 (s, 1H), 4.05-3.15 (m, 20H), 3.13 (s, 1H),2.70-2.35 (m, 4H), 2.03 (s, 3H), 1.92-1.90 (m, 1H), 1.89-1.87 (m, 2H),1.71-1.67 (m, 2H), 1.53-1.45 (m, 3H), 0.97 (s, 6H).

Example 8 Preparation of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide

Synthesis of4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide.Into a 100-mL round-bottom flask, was placed4-fluoro-3-nitrobenzene-1-sulfonamide (1.43 g, 0.007 mmol, 1 equiv),1-[(2R)-1,4-dioxan-2-yl]methanamine hydrochloride (1 g, 6.510 mmol, 1equiv), THF (30 mL), Cs₂CO₃ (8.48 g, 0.026 mmol, 4 equiv). The resultingsolution was stirred overnight at 50° C. in an oil bath. The solids werecollected by filtration. The solid was dried in an oven under reducedpressure. This resulted in 1.8 g (87.14%) of4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide asa yellow solid. LC-MS: (ES, m/z): M+1=318, R,T=0.740 min. ee=99%,[a]=+10.9 (C=0.103 g in 100 ml DMSO, T=27° C.).

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate. Into a100-mL round-bottom flask purged and maintained with an inert atmosphereof nitrogen, was placed methyl2-bromo-4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)benzoate(4.35 g, 8.21 mmol, 1.87 equiv), toluene (50 mL),4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraene (1.4 g, 4.39 mmol, 1equiv), Cs₂CO₃ (7.1 g, 21.85 mmol, 4.98 equiv), XantPhos Pd 2G (584 mg,0.66 mmol, 0.15 equiv). The resulting solution was stirred overnight at110° C. The resulting solution was diluted with 300 mL of water. Theresulting solution was extracted with 2×100 mL of ethyl acetate. Theresulting mixture was washed with 1×300 mL of brine. The mixture wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2). This resulted in 2.1 g (62%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl)benzoate as a brownsolid. LC-MS: (ES, m/z): M+H=770, R,T=1.318 min.

Synthesis of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate. Into a 40-mLvial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-(4-[[2-(trimethylsilyl)ethoxy]methyl]-14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-1 (2.1 g, 3.29 mmol, 1equiv), THF (20 mL), TBAF.3H₂O (5 g), ethane-1,2-diamine (1.4 g). Theresulting solution was stirred overnight at 70° C. in an oil bath. Theresulting solution was diluted with 200 mL of water. The resultingsolution was extracted with 3×30 mL of ethyl acetate. The resultingmixture was washed with 2×200 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under vacuum. The residue wasrecrystallization with ethyl acetate/petroleum ether (1:5). Thisresulted in 1.4 g (80%) of methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate as a whitesolid. LC-MS: (ES, m/z): M+H=640, R,T=1.023 min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid. Into a40-mL vial, was placed methyl4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoate (1.4 g, 2.24mmol, 1 equiv), EtOH (25 mL), dioxane (25 mL), 4M NaOH (5 mL). Theresulting solution was stirred for 4 h at 80° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The pH value of thesolution was adjusted to 5-6 with HCl (2 mol/L). The solids werecollected by filtration. This resulted in 1.1 g (80%) of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid as awhite solid. LC-MS: (ES, m/z): M+H=626, R,T=2.138 min.

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide. Into a40-mL vial, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (150 mg,0.240 mmol, 1 equiv), DCM (3 mL),4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide (76mg, 0.240 mmol, 1.00 equiv), EDCI (92 mg, 0.480 mmol, 2.00 equiv), DMAP(117 mg, 0.958 mmol, 4.00 equiv). The resulting solution was stirredovernight at 25° C. The resulting mixture was concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions (2 #SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBDColumn-5 um,19*150 mm; mobile phase, ACN and Water (0.05% NH₃.H₂O) (20%Phase B up to 75% in 1 min, up to 95% in 7 min, hold 95% in 1 min, downto 20% in 1 min); Detector, 254/220 nm. This resulted in 28 mg (12.63%)of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2R)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellowsolid. LC-MS: (ES, m/z): M+1=925, ee=100%, [a]=+7.4 (C=0.106 g/100 mL inCH₂Cl₂, T=27° C.), R,T=3.425 min. The measurements of the retention weredone with a reversed phase column (C18). Shimadzu LCMS 2020; 50*3.0SUPELCO Ascentis Express C18, 2.7 um; Eluent A: water (0.05% TFA);Eluent B: Acetonitrile; linear gradient from 5% acetonitrile to 95%acetonitrile in 7.0 minutes; Oven temperature 40° C.; flow: 1.5 mL/min.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 11.90 (s, 1H), 11.20 (s, 1H), 8.60-8.41(m, 2H), 7.64 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.36 (d, J=8.1Hz, 2H), 7.20 (t, J=2.9 Hz, 1H), 7.07 (d, J=8.1 Hz, 2H), 6.90 (d, J=12.1Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 6.19-6.06 (m, 1H), 4.20 (d, J=6.5 Hz,2H), 3.88-3.71 (m, 3H), 3.69-3.32 (m, 8H), 3.28 (s, 0H), 3.20 (s, 4H),2.78 (s, 2H), 2.22 (d, J=18.1 Hz, 6H), 1.98 (s, 4H), 1.51-1.34 (m, 2H),0.95 (s, 6H).

Example 9 Preparation of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide

Synthesis of4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide.Into a 100-mL round-bottom flask, was placed4-fluoro-3-nitrobenzene-1-sulfonamide (1.43 g, 0.007 mmol, 1 equiv),1-[(2S)-1,4-dioxan-2-yl]methanamine hydrochloride (1 g, 6.510 mmol, 1equiv), THF (30 mL), Cs₂CO₃ (8.48 g, 0.026 mmol, 4 equiv). The resultingsolution was stirred overnight at 50° C. in an oil bath. The solids werecollected by filtration. The solid was dried in an oven under reducedpressure. This resulted in 1.82 g (88.10%) of4-([[(25)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide asa yellow solid. LC-MS: (ES, m/z): M+1=318, R,T=0.741 min. ee=99%,[a]=−17.4 (C=0.102 g in 100 ml DMSO, T=27° C.).

Synthesis of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(25)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide. Into a40-mL vial, was placed4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzoic acid (150 mg,0.240 mmol, 1 equiv), DCM (3 mL),4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzene-1-sulfonamide (76mg, 0.240 mmol, 1.00 equiv), EDCI (92 mg, 0.480 mmol, 2.00 equiv), DMAP(117 mg, 0.958 mmol, 4.00 equiv). The resulting solution was stirredovernight at 25° C. The resulting mixture was concentrated under vacuum.The crude product was purified by Prep-HPLC with the followingconditions (2 #SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBDColumn-5 um,19*150 mm; mobile phase, ACN and Water (0.05% NH₃.H₂O) (20%Phase B up to 75% in 1 min, up to 95% in 7 min, hold 95% in 1 min, downto 20% in 1 min); Detector, 254/220 nm. This resulted in 29 mg (13.08%)of4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl)-N-[4-([[(2S)-1,4-dioxan-2-yl]methyl]amino)-3-nitrobenzenesulfonyl]-2-[14-oxa-2,4,10-triazatricyclo[7.5.0.0{circumflexover ( )}[3,7]]tetradeca-1(9),2,5,7-tetraen-10-yl]benzamide as a yellowsolid. LC-MS: (ES, m/z): M+1=925, R,T=3.426 min. ee=100%, [a]=−10.4(C=0.120 g/100 mL in CH₂Cl₂, T=27° C.). ¹H NMR (300 MHz, DMSO-d₆, ppm) δ11.90 (s, 1H), 11.20 (s, 1H), 8.60-8.41 (m, 2H), 7.64 (d, J=8.7 Hz, 1H),7.47 (d, J=8.7 Hz, 1H), 7.36 (d, J=8.1 Hz, 2H), 7.20 (t, J=2.9 Hz, 1H),7.07 (d, J=8.1 Hz, 2H), 6.90 (d, J=12.1 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H),6.19-6.06 (m, 1H), 4.20 (d, J=6.5 Hz, 2H), 3.88-3.71 (m, 3H), 3.69-3.32(m, 8H), 3.28 (s, 0H), 3.20 (s, 4H), 2.78 (s, 2H), 2.22 (d, J=18.1 Hz,6H), 1.98 (s, 4H), 1.51-1.34 (m, 2H), 0.95 (s, 6H).

The compounds below are prepared by methods substantially identical,similar, or analogous to those disclosed in above Schemes and Examples:

Example Chemical Name m/z(MH⁺) Cpd-1(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 943biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-2(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 943biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-3(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 937biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Cpd-4(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 955biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)- yl)benzamide Cpd-5N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3- 939nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-64-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 957biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)- yl)benzamide Cpd-7N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3- 939nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-84-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 957biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((S)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-9(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 937biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Cpd-10(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 955biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)- yl)benzamide Cpd-11N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3- 939nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-124-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 957biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((R)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)- yl)benzamide Cpd-13N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3- 939nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-144-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 957biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((S)-2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((R)-4-methyl-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-15(S)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 979biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-16(R)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 979biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((2-fluoro-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-17(R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3- 961nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-18(S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3- 961nitrophenyl)sulfonyl)-4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Cpd-194-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 959biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide Cpd-204-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 977biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(4,4-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Cpd-214-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′- 959biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

Biological Example 1 Bcl-2 Competition Binding (FluorescencePolarization) Assay

The fluorescence-labeled 23 amino acid peptide BH3 was purchased fromCalBiochem (NLWAAQRYGRELRRMSDKFVD). An unbound Fluorescein labeled BH3peptide emits random light with respect to the plane of polarizationplane of excited light, resulting in a lower polarization degree (mP)value. When the peptide is bound to Bcl-2, the complex tumble slower andthe emitted light can have a higher level of polarization, resulting ina higher mP value. This binding assay was performed in 96-well plate andwith each assay contained 15 and 30 nM of labeled peptide and purifiedBcl-2 protein (purchased from R&D Systems, Inc). The assay buffercontained 20 mM Hepes (pH 7.0), 50 mM KCl, 5 mM MgCl₂, 20 mM Na₂MoO₄,0.1 mg/ml Bovine Gamma Globulin and 0.01% NP40. Compounds were dilutedin DMSO and added to the final assay with concentration range from 20 μMto 2 nM. The polarization degree (mP) value was determined by BioTekSynergy II with background subtraction after 3 hours of incubation atroom temperature. IC₅₀ was calculated using Prism software withsigmoidal dose-response curve fitting. ABT-737 was used as referencecompound. Such assays, carried out with a range of doses of testcompounds, allowed the determination of an approximate IC₅₀ value.Although the inhibitory properties of the compounds of the presentinvention vary with structural change as expected, the activitygenerally exhibited by these agents was in the range of IC₅₀=0.1-1000nM.

Biological Example 2 In Vitro Anti-Proliferation Assay inBCL-2-Dependent Acute Lymphoblastic Leukemia (ALL) Cell Line RS4;11

Cell antiproliferation was assayed by PerkinElmer ATPlite™ LuminescenceAssay System. Briefly, the various test cancer cell lines were plated ata density of about 1×10⁴ cells per well in Costar 96-well plates, andwere incubated with different concentrations of compounds for about 72hours in medium supplemented with 5% FBS or 10% normal human serum(NHS).One lyophilized substrate solution vial was then reconstituted by adding5 mL of substrate buffer solution, and was agitated gently until thesolution was homogeneous. About 50 μL of mammalian cell lysis solutionwas added to 100 μL of cell suspension per well of a microplate, and theplate was shaken for about five minutes in an orbital shaker at ˜700rpm. This procedure was used to lyse the cells and to stabilize the ATP.Next, 50 μL substrate solution was added to the wells and microplate wasshaken for five minutes in an orbital shaker at ˜700 rpm. Finally, theluminescence was measured by a PerkinElmer TopCount® MicroplateScintillation Counter. Such assays, carried out with a range of doses oftest compounds, allowed the determination of the cellularanti-antiproliferative IC₅₀ of the compounds of the present invention.The following table lists the IC₅₀ values of certain compounds of theinvention. As shown below, Example 3 is significantly more potent thanboth NW-4-8 (Example 2) as well as ABT-199.

The following table lists the IC₅₀ values of another study for certaincompounds of the invention.

Compound IC50, RS4; 11 5% FBS ABT-199  5.8 nM Example 2 0.12 nM Example3 <0.1 nM

Biological Example 3 In Vitro Anti-Proliferation Assay in Small CellLung Cancer (SCLC) Cell Line

Cell antiproliferation was assayed by PerkinElmer ATPlite™ LuminescenceAssay System. Briefly, the various test cancer cell lines were plated ata density of about 1×10⁴ cells per well in Costar 96-well plates, andwere incubated with different concentrations of compounds for about 72hours in medium supplemented with 5% FBS. One lyophilized substratesolution vial was then reconstituted by adding 5 mL of substrate buffersolution, and was agitated gently until the solution was homogeneous.About 50 μL of mammalian cell lysis solution was added to 100 μL of cellsuspension per well of a microplate, and the plate was shaken for aboutfive minutes in an orbital shaker at ˜700 rpm. This procedure was usedto lyse the cells and to stabilize the ATP. Next, 50 μL substratesolution was added to the wells and microplate was shaken for fiveminutes in an orbital shaker at ˜700 rpm. Finally, the luminescence wasmeasured by a PerkinElmer TopCount® Microplate Scintillation Counter.Such assays, carried out with a range of doses of test compounds,allowed the determination of the cellular anti-antiproliferative IC₅₀ ofthe compounds of the present invention. The following table lists theIC₅₀ values of several cancer cell lines (5% FBS) for certain compoundsof the invention.

Compound IC50, Toledo IC50, MV411 IC50, Granta ABT-199 98.1 nM 20.1 nM42.5 nM Example 2  8.1 nM  1.6 nM  3.5 nM

The following table lists the IC₅₀ values of several small cell lungcancer cell lines (5% FBS) for certain compounds of the invention.Cisplatin, the standard of Care of small cell lung cancer cell lines wasused as the positive control drug.

Compound IC50, H146 IC50, H889 IC50, H1963 Cisplatin 4,588 nM 7,083 nM1,674 nM ABT-263 28 nM 32.4 nM 41.7 nM Example 2 64 nM 1.0 nM 5.6 nMExample 3 43 nM 0.9 nM 4.2 nM Example 8 50 nM 0.7 nM 5.3 nM Example 9 33nM 0.7 nM 4.7 nM

Biological Example 4 Mice PK Study

The pharmacokinetics of compounds were evaluated in CD-1 mouse viaIntravenous and Oral Administration. The IV dose was administered as aslow bolus in the Jugular vein, and oral doses were administered bygavage. The formulation for IV dosing was 5% DMSO in 20% HPBCD in water,and the PO formulation was 2.5% DMSO, 10% EtOH, 20% Cremphor EL, 67.5%D5W. The PK time point for the IV arm was 5, 15, 30 min, 1, 2, 4, 6, 8,12, 24 hours post dose, and for PO arm was 15, 30 min, 1, 2, 4, 6, 8,12, 24 hours post dose. Approximately 0.03 mL blood was collected ateach time point. Blood of each sample was transferred into plastic microcentrifuge tubes containing EDTA-K2 and collect plasma within 15 min bycentrifugation at 4000 g for 5 minutes in a 4° C. centrifuge. Plasmasamples were stored in polypropylene tubes. The samples were stored in afreezer at −75±15° C. prior to analysis. Concentrations of compounds inthe plasma samples were analyzed using a LC-MS/MS method. WinNonlin(Phoenix™, version 6.1) or other similar software was used forpharmacokinetic calculations. The following pharmacokinetic parameterswere calculated, whenever possible from the plasma concentration versustime data: IV administration: C₀, CL, V_(d), T_(1/2), AUC_(inf),AUC_(Iast), MRT, Number of Points for Regression; PO administration:C_(max), T_(max), T_(1/2), AUC_(inf), AUC_(Iast), F %, Number of Pointsfor Regression. The pharmacokinetic data was described using descriptivestatistics such as mean, standard deviation. Additional pharmacokineticor statistical analysis was performed at the discretion of thecontributing scientist, and was documented in the data summary. The PKresults of oral dosing of po, 10 mg/kg is shown in the Table below.

Compound AUC_(last)(h*ng/mL) t ½ (hour) Bioavailabilty Example 2 9,3044.3 49% Example 3 4,158 2.6 30% Example 8 5,714 2.3 44% Example 9 8,1682.3 64%

For comparison purpose, the PK results of oral dosing of po, 10 mg/kg ofcertain compounds in WO/2017/132474 is shown in the Table below.

Compound AUC(h*ng/mL) Example 12 in WO/2017/132474 1,088 Example 16 inWO/2017/132474 849 Example 18 in WO/2017/132474 1,890

Biological Example 5 In Vivo Xenograft Studies

Compound of Example 3 is selected for in vivo studies in theBCL-2-dependent acute lymphoblastic leukemia (ALL) RS4;11 xenograftmodel. The CB.17 SCID mice are obtained at age 6-8 weeks from vendorsand acclimated for a minimum 7-day period. The cancer cells are thenimplanted into the nude mice. Depending on the specific tumor type,tumors are typically detectable about two weeks following implantation.When tumor sizes reach ˜100-200 mm³, the animals with appreciable tumorsize and shape are randomly assigned into groups of 8 mice each,including one vehicle control group and treatment groups. Dosing variesdepending on the purpose and length of each study, which typicallyproceeds for about 3-4 weeks. Tumor sizes and body weight are typicallymeasured three times per week. In addition to the determination of tumorsize changes, the last tumor measurement is used to generate the tumorsize change ratio (T/C value), a standard metric developed by theNational Cancer Institute for xenograft tumor evaluation. In most cases,% T/C values are calculated using the following formula: % T/C=100×ΔT/ΔCif ΔT>0. When tumor regression occurred (ΔT<0), however, the followingformula is used: % T/T0=100×ΔT/T0. Values of <42% are consideredsignificant.

What is claimed is:
 1. A compound, an N-oxide thereof, or apharmaceutically acceptable salt, solvate, polymorph, tautomer,stereoisomer, isotopic form, or a prodrug thereof, wherein said compoundis4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.2. A compound or a pharmaceutically acceptable salt thereof, whereinsaid compound is4-(4-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-2-(3,3-difluoro-3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.3. A pharmaceutical composition comprising the compound of claim 2 orpharmaceutically acceptable salt thereof.